NZ509636A

NZ509636A - New piperidine-4-sulphonamides compounds, a process for their preparation and pharmaceutical compositions containing them useful for treating disease caused by endothelial dysfunction

Info

Publication number: NZ509636A
Application number: NZ509636A
Authority: NZ
Inventors: Jean-Louis Peglion; Aimee Dessinges; Christophe Poitevin; Jean-Paul Vilaine; Nicole Villeneuve; Catherine Thollon; Marie-Pierre Bourguignon
Original assignee: Adir
Priority date: 2000-01-31
Filing date: 2001-01-30
Publication date: 2001-09-28
Also published as: JP2001233874A; EP1122254A3; PL345528A1; ZA200100864B; EA003096B1; DK1122254T3; HUP0100489A2; CN1314345A; US6323217B2; CA2332513A1; HK1039117A1; NO320387B1; ES2241757T3; CA2332513C; NO20010522L; HU0100489D0; HUP0100489A3; DE60110278T2; BR0100234A; MXPA01000945A

Abstract

Piperidine-4-sulphonamide compounds of formula (I), the process for their preparation and their use in treating endothelial disorders is disclosed. Such endothelial disorders include atherosclerotic lesions, vascular complications following vascular bypass, vascular dilation, vascular repermeabilisation, heart transplant, myocardial disorders, peripheral ischaemia, cardiac insufficiency and pulmonary arterial hypertension.

Description

<div class="application article clearfix" id="description"> 509636 NEW ZEALAND PATENTS ACT, 1953 No. Date: COMPLETE SPECIFICATION NEW PIPERIDINE-4-SULPHONAMIDES COMPOUNDS, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM We, ADIR ET COMPAGNIE, a French body corporate of 1, rue Carle Hebert, 92415 Courbevoie Cedex, France, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described m and by the following statement: -1 - (followed by page 1A) INTELLECTUAL PROPERTY ! OFFICE Or nv 3 0 JAN 2C01 - 1A- The present invention relates to new piperidine-4-sulphonamide compounds, to a process for their preparation and to pharmaceutical compositions containing them. The compounds of the present invention are useful in the treatment of diseases or pathological conditions in which endothelial dysfunction is known to be a pathogenic 5 and/or aggravating mechanism. Such pathologies are : atherosclerosis, the existence of vascular risk factors (dyslipidaemia, diabetes, systemic arterial hypertension), the various clinical forms of myocardial or peripheral ischaemia, cardiac insufficiency and the various forms of pulmonary arterial hypertension. Such compounds are also useful in the treatment of patients undergoing heart transplantation or vascular repermeabilisation such as a 10 bypass, thrombolysis or arterial dilatation with or without a stent. A reduction in the vascular availability of nitrogen monoxide (NO) constitutes the major mechanism of endothelial dysfunction observed in the diseases and pathological conditions mentioned above and explains its pathogenic role (Cardiovasc Res, 1999, 43, 572 ; Coronary. Art. Dis. 1999, 10, 277 ; Coronary. Art. Dis., 1999, 10, 301 ; Coronary. Art. 15 Dis., 1999, 10, 287 ; Coronary. Art. Dis., 1999,10, 295). In those pathological conditions, the endothelial dysfunction may in fact result from two main mechanisms: 1) inadequate production of NO associated with inhibition of endothelial NO synthase by endogenous inhibitors such as ADMA (asymmetric dimethyl-arginine), the plasma concentration of which increases in patients exhibiting cardiovascular 20 risk factors (Cardiovasc Res., 1999, 43, 542 ; Hypertension, 1997, 29, 242 ; Circulation, 1997, 95, 2068), 2) inactivation of NO by the superoxide anion (O2"), the production of which is increased in pathological conditions (Cardiovasc Res, 1999, 43, 562 ; Eur. J Biochem. 1997, 245, 541 ; J Clin Invest, 1993, 912546). Under normal conditions, NO produces major effects such as: 1) regulation of arterial 25 vasomotricity by means of its vasodilator effect (N Engl. J Med, 1993, 329. 2002 ; Nature, 1980, 288, 373), 2) limitation of platelet adhesion and aggregation (Trends Pharmacol ScL, 1991,12, 87), 3) control of the adhesion of leukocytes and monocytes to endothelial -2- cells (Proc. Natl Acad Sci. USA, 1991, 88, 4651), 4) inhibition of the proliferation of vascular smooth muscle cells (Cardiovasc. Res., 1999, 43, 580, Circulation, 1993, 87 V51), which explains why the deficiency of NO in the arterial wall is favourable to pathological phenomena such as vasoconstriction, thrombosis, lipid accumulation and 5 proliferation of vascular smooth muscle cells. In vitro experiments have enabled it to be shown that the compounds of the present invention enable limitation of the endothelial dysfunction and of the reduced vascular availability of NO induced by tests involving the two physiopathological mechanisms already mentioned: inhibition of endothelial NO synthase and oxidative stress due to 10 production of O2". Thus, in addition to the fact that they are new, by virtue of their specific pharmacological activity, which is capable of limiting the development of endothelial dysfunction, the compounds of the present invention are useful in preventing the development, extension and complications of atherosclerotic lesions, especially in patients exhibiting a vascular 15 risk factor (dyslipidaemia, diabetes, arterial hypertension), and in treating the various clinical forms of myocardial or peripheral ischaemia, cardiac insufficiency and the various forms of pulmonary arterial hypertension. The compounds are also used for preventing vascular complications (spasm, thrombosis, restenosis, accelerated atherosclerosis) in patients undergoing a bypass, vascular dilatation with or without a stent or other forms of 20 vascular repermeabilisation and also heart transplantation. Compounds of similar structure have been described in the literature, that being the case, more especially, for Patent Application WO 94/13659, which claims especially piperidine-benzofurane compounds. Such compounds are useful in the treatment and/or prophylaxis of arrhythmia. They are distinguished clearly from the compounds of the present invention 25 by their chemical structure and especially by the absence of the sulphonamide function, and by their pharmacological properties. Patent Specification EP 0 526 342 describes new (isoquinolin-5-yl)sulphonamides and claims those compounds for their usefulness in the treatment and prevention of disorders resulting from tissue pain phenomena. More especially, the present invention relates to compounds of formula (I): W-SO—NR—U- R3 «2b (I) wherein: ri represents a hydrogen atom or a linear or branched (Ci-C6)alkyl group, ri« and r2b, which may be identical or different, each independently of the other represents a group selected from a hydrogen atom, a halogen atom, a linear or branched (Ci-C6)alkyl group, a hydroxy group, a linear or branched (Ci-C6)alkoxy group, a linear or branched (Ci-C6)trihaloalkyl group, a cyano group, a nitro group, an amino group, a linear or branched (Ci-C6)alkylamino group, and a di-(Ci-C6)-alkylamino group in which each alkyl moiety is linear or branched, R3 represents a hydrogen atom or a hydroxy group, X represents an oxygen atom or a methylene group, v represents a linear or branched (Ci-C6)alkylene chain optionally containing one or more unsaturations and being optionally substituted by one or more identical or different groups selected from halogen atoms, hydroxy groups and linear or branched (Ci-C6)alkoxy groups, U represents a bond or a linear or branched (Ci-C6)alkylene chain, w represents a group selected from aryl and heteroaryl, each of those groups being optionally substituted by one or more identical or different groups selected from halogen atoms, linear or branched (Ci-C6)alkyl groups, hydroxy groups, linear or branched (Ci-C6)alkoxy groups, linear or branched (Ci-C6)trihaloalkyl groups, oxo groups, cyano groups, nitro groups, amino groups, linear or branched (Cj-Ce)-alkylamino groups, di-(CpC6)alkylamino groups in which each alkyl moiety is linear or branched, pyridyl groups, linear or branched (Ci-C6)alkylcarbonyl groups, aminocarbonyl groups (the amino moiety being optionally substituted by one or two identical or different linear or branched (Ci-C6)alkyl groups), linear or branched (Ci-C6)alkoxycarbonyl groups, linear or branched (Ci-C6)trihaloalkylcarbonyl groups, linear or branched (Ci-C6)alkylsulphonyl groups, and linear or branched (Ci-Ct)- trihaloalkylsulphonyl groups, their isomers, their hydrates, their solvates and addition salts thereof with a pharmaceutically acceptable acid or base, it being understood that: - "aryl group" is understood to mean a group selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl and indenyl, - "heteroaryl group" is understood to mean a monocyclic aromatic or bicyclic system having from 5 to 12 ring members and containing from 1 to 3 identical or different hetero atoms selected from oxygen, nitrogen and sulphur, and in the case of a bicyclic system one of the rings has an aromatic character, it being possible for the other ring to be aromatic or partially hydrogenated. Among the heteroaryl groups there may be mentioned by way of non-limiting example the groups pyridyl, pyrazolyl, isoxazolyl, dihydroisoxazolyl, quinolyl, isoquinolyl, tetrahydroisoquinolyl, benzofurazanyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, 2,1,3-benzoxodiazolyl, 2,1,3-benzothiadiazolyl, thieno[2,3-c]pyridyl, furo[2,3-c] pyridyl, etc.. Among the pharmaceutically acceptable bases there may be mentioned by way of non-limiting example sodium hydroxide, potassium hydroxide, triethylamine, terf-butylamine, etc.. Among the pharmaceutically acceptable acids there may be mentioned by way of non-limiting example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutamic acid, fumaric acid, tartaric acid, dibenzoyltartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, camphoric acid, etc. The preferred substituent X according to the invention is the oxygen atom. The preferred substituents Rj according to the invention are the hydrogen atom and the methyl group. According to an advantageous embodiment, the preferred compounds of the invention are compounds of formula (i/a): W-SO—NH—U N—V- / r^21 Rib wherein W, U, V, R.2a and R2b are as defined for formula (I). (i/a) Advantageously, the preferred substituent W according to the invention is the isoquinolin-5-yl group. According to another embodiment of the invention, the preferred substituent W is the group l,2,3,4-tetrahydro-isoquinolin-5-yl optionally substituted in the 2-position by a group of formula -C(0)-A wherein A represents a group selected from linear or branched (Ci-C6)alkyl, amino (itself optionally substituted by one or two identical or different linear or branched (Ci-C6)alkyl groups), linear or branched (Ci-C6)alkoxy, trifluoromethyl, linear or branched (Ci-C6)alkylsulphonyl, and trifluoromethylsulphonyl. Especially advantageously, the preferred compounds of the invention are the compounds of formula (I/A) as defined hereinbefore wherein U, V, R23 and R2b are as defined for formula (I) and W represents an isoquinolin-5-yl group. According to another especially advantageous embodiment, the preferred compounds of the invention are the compounds of formula (I/A) as defined hereinbefore wherein U, V, R2a and R2b are as defined for formula (I) and W represents a 1,2,3,4-tetrahydroisoquinolin-5-yl group optionally substituted in the 2-position by a group of formula -C(0)A wherein A is as defined hereinbefore. The preferred compounds of the invention are : - jV-{l-[2-(benzofuran-3-yl)ethyl]-4-piperidyl}-(isoquinolin-5-yl)sulphonamide, - ethyl 5- {[({(1 - [2-(benzofuran-3 -yl)ethyl] -4-piperidyl} methyl)-(methyl)amino] -sulphonyl} -3,4-dihydro-2( 1 //)-isoquinolinecarboxylate, - N-({2-[2-benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl}ethyl)-5-isoquinoline-sulphonamide, - A^-({l-[2-(benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl}methyl)-7V-methyl-2,l,3-benzoxadiazole-4-sulphonamide, and - isopropyl 5-{[({ l-[2-(benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-(methyl)amino]-sulphonyl} -3,4-dihydro-2( 1 //)-isoquinolinecarboxylate. The isomers, hydrates, solvates and addition salts thereof with a pharmaceutically acceptable acid or base of the preferred compounds form an integral part of the invention. The invention relates also to a process for the preparation of compounds of formula (i), characterised in that there is used as starting material a compound of formula (ii) : wherein X, R.2a and R2b are as defined for formula (I), Vj represents a bond or a linear or branched (Ci-Cs)alkylene chain optionally containing one or more unsaturations, R5 represents a hydrogen atom, a chlorine atom, a hydroxy group or a linear or branched (Ci-C6)alkoxy group, which compounds of formula (II) are reacted : 4 either with a compound of formula (iii/a) : (id (iii/a) to yield compounds of formula (iv): (IV) wherein R2a, R2b, X and V1 are as defined hereinbefore, -7- the ketal function of which compounds of formula (iv) is deprotected in accordance with conventional techniques of organic synthesis, and which are then reacted under conditions of reductive amination with a compound of formula (v) : r'i - nh2 (v) wherein r'i represents a linear or branched (Ci-C6)alkyl group, to yield compounds of formula (vi/a) : •i-nh-( ; r',- 0 (vl/a) *2b wherein R'i, R2a, R2b, X and Vi are as defined hereinbefore, 4 or with a compound of formula (iii/b) : 10 HN V NHBoc (iii/b) wherein Boc represents a /err-butoxycarbonyl group, to yield compounds of formula (vii) : BocHN—/ V. .Vr(F ^ (vii) ^b wherein Boc, R2a, R2b, X and Vi are as defined hereinbefore, the terminal amine function 15 of which compounds of formula (VII) is deprotected to yield compounds of formula (vi/b) : , ,Vr h2n / T o x Xb (vi/b) wherein R2a, R2b, V i and X are as defined hereinbefore, the totality of the compounds of formulae (VI/A) and (VI/B) constituting the compounds 20 of formula (vi): -8- 10 R, - NH <^>K (VI) 0 " wherein Ri is as defined for formula (I) and R2a, R2b, X and Vj are as defined hereinbefore, which compounds of formula (VI) are treated with one of the reducing agents currently used in organic synthesis to reduce amide functions, to yield compounds of formula (VIII): R, - NH \ / (VIII) Rab wherein Rj, V], X, R2a and R2b are as defined hereinbefore, which compounds of formula (VIII) are treated with a compound of formula (IX) : W - S02C1 (IX) wherein W is as defined for formula (I), to yield compounds of formula (I/a), a particular case of the compounds of formula (I): R, , , V w—SO—N \ Vv' nT^I (I/a) ^2b wherein W, Ri, Vi, X, R2aand R2b are as defined hereinbefore, 4 or with a compound of formula (III/C) : H02C-Ur 15 NH (III/C) wherein Ui represents a bond or a linear or branched (Ci-Cs)alkylene chain, to yield compounds of formula (X) : (X) H02C-U, \ N. .V T 1 0 " wherein Ui, Vi, X, R2a and R2b are as defined hereinbefore, 9- 10 15 which compounds of formula (X) are treated with ammonium hydroxide or with a compound of formula (V) as defined hereinbefore in the presence of a coupling agent, such as dicyclohexylcarbodiimide, carbonyldiimidazole or 1,1,1,3,3,3-hexamethyldisylazane, to yield compounds of formula (XI): R, - NH (XI) T Y oo % wherein Ri is as defined for formula (I), and Ui, Vi, X, R2a and R2b are as defined hereinbefore, which compounds of formula (XI) are reduced in accordance with conventional conditions of organic synthesis, to yield compounds of formula (XII): Aa r rf" ^ *Vr Rj-NH-U2 nf^l x-W (XII) wherein U2 represents a linear or branched (Ci-C6)alkylene chain, and Ri, Vi, X, R2a and R2b are as defined hereinbefore, which compounds of formula (XII) are reacted with a compound of formula (IX), as defined hereinbefore, to yield compounds of formula (I/b), a particular case of the compounds of formula (I): w—SO—N—u2 (I/b) wherein W, Ri, U2, Vi, X, R2a and R2b are as defined hereinbefore, 4 or the terminal carbonyl group of which compounds of formula (II), which group is substituted by a group R'5 having the meanings of R5 as defined hereinbefore with the 20 exception of the meaning "chlorine atom", is reduced, the resulting hydroxy group of which is then replaced by a halogen atom, such as CI, Br or I, using customary techniques of organic chemistry, to yield compounds of formula (II/B): -10- 10 15 R, 4~V - Hal (II/B) X' wherein X and V are as defined for formula (I) and Hal represents a halogen atom, which compound of formula (II/B) is added to a compound of formula (III/D): .OH (III/D) U2 - NH - C02Et wherein U2 is as defined hereinbefore, to yield compounds of formula (XIII) : Et02C - NH - U2 HO \ / ^ (XIII) wherein U2, V, X, R2a and R2b are as defined hereinbefore, which compounds of formula (XIII) are treated with a reducing agent or with a strong alkaline base, to yield compounds of formula (XIV) : Aa (XIV) R. - NH - U, la l ' X>v-c HO \ / \ wherein Ria represents a hydrogen atom or a methyl group, and U2, V, X, R2a and R2b are as defined hereinbefore, which compounds of formula (XIV) are treated with a compound of formula (IX), to yield compounds of formula (I/c), a particular case of the compounds of formula (I): Ria Aa (I/c) W - S02 - N - u2 2xT/-v^ HO \ / \ X R2b wherein W, Rla, U2, V, X, R2a and R2b are as defined hereinbefore, 4 or which compound of formula (II), in the particular case when R5 represents a hydrogen -11 - 10 atom and Vi has the meaning V'i representing a linear or branched (Ci-C4)alkylene chain, is treated with trimethylsulphoxonium iodide in the presence of sodium hydride in dimethyl sulphoxide, to yield compounds of formula (ii/c): Raa 1^—L (ii/c) wherein R2a, R2b, X and V'i are as defined hereinbefore, which compounds of formula (II/C) are reacted with any one of the compounds of formulae (III/A), (III/B) and (III/C), the resulting intermediates then being deprotected and functionalised in accordance with the respective methods described hereinbefore, to yield compounds of formula (xv) : R, - NH - U N- / -V: OH Raa (xv) *2b wherein Ri, U, X, R2a and R2b are as defined hereinbefore and V'i is as defined hereinbefore, 4 or which compound of formula (II), in the particular case when it represents a compound of formula (ii/d) : wherein R2a, R2b and X are as defined for formula (I), is reacted with any one of the compounds of formulae (III/A), (III/B) and (III/C), the resulting intermediates then being deprotected and functionalised in accordance with the respective methods hereinbefore, 20 to yield compounds of formula (xvi): R, - NH ■-O -12- ~t^ o- (xvi) ^b wherein Ri, U, X, R2a and R2b are as defined hereinbefore, which compounds of formula (XVI) are reduced in conventional manner to yield compounds of formula (xvii) : R, - NH - U- "Y N J lf^ HO R2a (xvii) the totality of the compounds of formulae (XV) and (XVII) constituting the compounds of formula (xviii) : R, - NH - U (xviii) wherein Ri, U, X, R2a and R2b are as defined hereinbefore, and V'ia represents a bond or a linear or branched (CpC^alkylene chain, the hydroxy function of which compounds of formula (XVIII) is replaced, if desired, by a halogen atom, in accordance with conventional conditions of organic synthesis, to yield compounds of formula (XIX): R, - NH - U^Y -V' la Hal' R2a (xix) Rab wherein Hal represents a halogen atom, and Ri, U, V'ia, X, R2a and R2b are as defined hereinbefore, the totality of the compounds of formulae (XVIII) and (XIX) being reacted with a compound of formula (IX) as described hereinbefore, to yield compounds of formula (I/d), -13- a particular case of the compounds of formula (I) R, W - S02 - N - U (I/d) wherein W, Rj, U, X, R2a and R2b are as defined for formula (I), V'ia is as defined hereinbefore and R$ represents a hydroxy group or a halogen atom, 5 which compounds of formula (I/d), in the particular case when R$ represents a hydroxy group, are subjected to the action of an alkylating agent in accordance with conventional conditions of organic chemistry, to yield compounds of formula (I/e), a particular case of the compounds of formula (I): T1 A~\ w-S0i-N-u-O~vv.jrir<*f" <I/e) r/ ^2b 10 wherein W, Ri, U, V'ia, X, R2a and R2b are as defined hereinbefore and R7 represents a linear or branched (Ci-C6)alkyl group, which compounds of formulae (I/a) to (I/e) constitute the totality of the compounds of the invention, which are purified, if necessary, in accordance with conventional purification techniques, which may be separated, if desired, into their different isomers in accordance 15 with a conventional separation technique, the substituents R2a and R2b of which and those of the group W being transformed in accordance with conventional methods of organic synthesis used in the field of aromatic chemistry, the W group of which, when it is a bicyclic system, is reduced, if desired, to yield bicyclic W groups, one of whose rings is partially hydrogenated and which may then be substituted in accordance with conventional 20 conditions of organic chemistry, and which are converted, if desired, into their addition salts with a pharmaceutically acceptable acid or base, and which may be in the form of hydrates or solvates. -14- The compounds of formulae (II), (III/A), (III/B), (III/C), (III/D), (V) and (IX) are either commercial products or are obtained according to known conventional methods of organic synthesis. The compounds of the present invention are useful in the treatment of diseases or 5 pathological conditions in which endothelial dysfunction is known. Owing to their specific pharmacological activity, the compounds of the invention are accordingly useful in preventing the development, extension and complications of atherosclerotic lesions, in the treatment of myocardial or peripheral ischaemia, cardiac insufficiency, pulmonary arterial hypertension, in the prevention of vascular complications after vascular bypass, vascular | 10 dilatation, vascular repermeabilisation and heart transplantation. The present invention relates also to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I), its optical isomers, its hydrates, its solvates, and addition salts thereof with a pharmaceutically acceptable acid or base, alone or in combination with one or more inert, non-toxic, pharmaceutically acceptable 15 excipients or carriers. Among the pharmaceutical compositions according to the invention, there may be mentioned more especially those that are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), per- or trans-cutaneous, nasal, rectal, perlingual, ocular or respiratory administration, and especially tablets or dragees, sublingual tablets, gelatin 20 capsules, capsules, suppositories, creams, ointments, dermal gels, injectable or drinkable preparations, aerosols, eye or nose drops, etc.. The useful dosage varies according to the age and weight of the patient, the route of administration, the nature and severity of the disorder, and whether any associated treatments are being taken, and ranges from 1 mg to 200 mg in one or more 25 administrations per day. The following Examples illustrate the invention but do not limit it in any way. The starting materials used are known products or are prepared according to known procedures. The -15- various Preparations yield synthesis intermediates for use in the preparation of the compounds of the invention. The structures of the compounds described in the Examples were determined according to the usual spectrophotometric techniques (infrared, nuclear magnetic resonance, mass 5 spectrometry, etc.). The melting points were determined using a Kofler hotplate (K.), or using a hotplate under a microscope (M.K.). When the compound exists in the form of a salt, the melting point given corresponds to that of the salt. PREPARATION 1 : 10 Ar-({l-[2-(Benzofuran-3-yl)ethyI]-4-piperidyl}methyl)-A7-methy]amine Step A : Ethyl l-(benzofuran-3-ylacetyl)-4-piperidinecarboxylate 22 g of carbonyldiimidazole are added in portions to 23.9 g of benzofuran-3-ylacetic acid in 250 ml of dichloromethane. When the evolution of gas has stopped, the reaction mixture is stirred for 1 hour and then 21 ml of ethyl piperid-4-ylcarboxylate are added dropwise. 15 After 12 hours' stirring at room temperature, the reaction mixture is washed with IN sodium hydroxide solution and then with IN hydrochloric acid. After decanting and drying, concentration under reduced pressure enables the expected product to be isolated. Step B: l-(Benzofuran-3-ylacetyl)-4-piperidinecarboxylic acid 200 ml of IN sodium hydroxide solution are added to a solution of 42.1 g of the product 20 obtained in Step A in 200 ml of ethanol. After 8 hours' stirring at room temperature, the ethanol is removed by evaporation, the mixture is washed with ether, and the aqueous phase is rendered acidic with IN hydrochloric acid. After extraction with dichloromethane, decanting and drying, concentration under reduced pressure enables the expected product to be isolated. -16- Stev C: l-(Benzofuran-3-ylacetyl)-N-methyl-4-piperidinecarboxamide 19 g of carbonyldiimidazole are added in portions to 33 g of the product obtained in Step B in 350 ml of dichloromethane. When the evolution of gas has stopped, the reaction mixture is stirred for 1 hour at room temperature and then a stream of methylamine is circulated 5 through it. After 12 hours' stirring, the mixture is diluted with water, decanted, washed with IN sodium hydroxide solution and then with IN hydrochloric acid, decanted, dried and evaporated, enabling the expected product to be isolated. Step D: N-({l-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-N-methylamine 7.6 g of lithium aluminium hydride are added in portions to a solution of 28.7 g of the 10 product obtained in Step C in 1.5 litres of tetrahydrofuran heated at 60°C. After 18 hours at reflux, the reaction mixture is hydrolysed by the addition of 5.24 ml of water, 4.2 ml of 20% sodium hydroxide solution and then 19.2 ml of water. After filtration, drying and concentration under reduced pressure, the expected product is isolated. The hydrochloride thereof recrystallises from methanol. 15 Melting point (M.K.) : 270-280°C (decomposition) PREPARATION 2 : 7V-({l-[2-(Benzofuran-2-yl)ethyl]-4-piperidyI}methyI)-jV-methylamine The product is obtained according to the process of Preparation 1, using benzofuran-2-ylacetic acid as substrate in Step A. 20 PREPARATION 3 : {l-[2-(Benzofuran-3-y])ethyl]-4-piperidyl}-methylamine The product is obtained according to the process of Preparation 1, using a stream of ammonia instead of a stream of methylamine in Step C. -17- PREPARATION 4: Ar-({l-[2-(l-//-Inden-3-yl)ethyl]-4-piperidyI}methyI)-Ar-methyIamine The product is obtained according to the process of Preparation 1, using l//-inden-3-ylacetic acid as substrate in Step A. PREPARATION 5 : jV-({l-[(2£)-3-(Benzofuran-2-yl)-2-propenyl]-4-piperidyl}methyl)-iV-methylamine Step A : 3-(Benzofuran-2-yl)acrylic acid A mixture of 20 g of benzofuran-2-ylcarbaldehyde and 14.25 g of malonic acid in 13.8 ml of pyridine is heated at 100°C until the evolution of gas has stopped. After cooling, the expected product is precipitated with IN hydrochloric acid. The expected product is isolated by filtration, washing with hydrochloric acid and then with water, and drying. Step B: Ethyl l-[(2E)-3-(benzofuran-2-yl)-2-propenoyl]-4-piperidine-carboxylate 25 g of the acid chloride of the product obtained in Step A (obtained by the action of thionyl chloride) are slowly added at room temperature to a solution of 19 g of ethyl piperid-4-ylcarboxylate and 9.75 ml of pyridine in 250 ml of acetonitrile. After stirring for 1 hour, the reaction mixture is concentrated, taken up in ethyl acetate, washed with IN hydrochloric acid and then with 0.1N sodium hydroxide solution, dried and filtered. Concentration under reduced pressure enables the expected product to be isolated. Step C: N-({l-[(2E)-3-(Benzofuran-2-yl)-2-propenyl]-4-piperidyl}methyl)-N methylamine The product is obtained according to the process of Preparation 1, Steps B to D, using the product isolated in the preceding Step B as substrate in Step B. -18- PRF.PARATION 6 : l-[2-(Benzofuran-3-yl)ethyl]-Ar- methyI-4-piperidinamine Step A : 8-(Benzofuran-3-yI)-l,4-dioxa-8-azaspiro[4.5]decane The product is obtained according to Step A of Preparation 1 using l,4-dioxa-8-5 azaspiro[4.5]decane as reagent. Step B: l-(Benzofuran-3-ylacetyl)-piperidin-4-one 50 ml of IN hydrochloric acid are added to a solution of 5 g of the product obtained in Step A in 200 ml of acetone. After stirring for 1 hour 30 at room temperature, 50 ml of IN hydrochloric acid are again added and the mixture is heated for 2 hours at 50°C. After 10 cooling, the reaction mixture is neutralised by the addition of 100 ml of a 10 % sodium hydrogen carbonate solution and then concentrated, taken up in dichloromethane, washed with water, decanted and dried. Concentration under reduced pressure enables the expected product to be isolated. Step C: l-(Benzofuran-3-ylacetyl)-N-methyl-4-piperidinamine 15 A 33% solution of methylamine in ethanol is added dropwise to a solution of 13.7 g of the product obtained in Step B in 130 ml of isopropanol. After 2 hours at 10°C, 3.5 g of sodium hydroxide are added and stirring is maintained for 1 hour at room temperature. The reaction mixture is then cooled to 10°C and 2.8 g of sodium borohydnde are added. After 12 hours' stirring at room temperature, the reaction mixture is concentrated, taken up in 20 water and dichloromethane, decanted, dried and evaporated. Chromatography over silica gel (CH2Cl2/Me0H/NH40H : 95/5/0.5) enables the expected product to be isolated. Step D: l-[2-(Benzofuran-3-yl)ethyl]-N- methyl-4-piperidinamine 7.2 g of the product obtained in Step C are added to a suspension of 2 g of LiAlRj in 210 ml of tetrahydrofiiran. After 48 hours at room temperature, the reaction mixture is 25 hydrolysed with 1.4 ml of water, 1.1 ml of 20% sodium hydroxide solution and 5 ml of -19- water. After filtration and concentration, chromatography over silica gel enables the expected product to be isolated. Melting point (M.K.) : < 50°C PREPARATION 7 : 5 l-[2-(Benzofuran-3-yl)ethyl]-4-piperidinamine Step A : Tert-butyl l-[2-(benzofuran-3-yl)ethyl]-4-piperidylcarbamate 13 ml of acetic acid and 61 g of sodium triacetoxyborohydride are added in succession to a solution of 33 g of 2-(benzofuran-3-yl)acetaldehyde and 41.3 g of /erf-butyl 4-piperidylcarbamate in 1.4 litres of dichloromethane. After 24 hours' stirring at room 10 temperature, a 20% sodium hydroxide solution is added. After 10 minutes, the reaction mixture is decanted and the organic phase is washed, dried and concentrated. Chromatography over silica gel (cyclohexane/ethyl acetate : 30/70) enables the expected product to be isolated. Step B: l-[2-(Benzofuran-3-yl)ethyl]-4-piperidinamine 15 235 ml of a 2.9N ethanolic hydrogen chloride solution are added to a solution of 21 g of the product obtained in Step A in 786 ml of ethanol. After 3 hours at 70°C and then 16 hours at room temperature, the reaction mixture is concentrated under reduced pressure. The residue is taken up in 150 ml of water. The expected product is precipitated by the addition of 20 % sodium hydroxide solution 20 Melting point (K.) : 64-66°C PREPARATION 8 : l-[2-(l//-Inden-3-yl)ethyl]-4-piperidinamine Step A: l-(lH-Inden-3-ylacetyl)piperidin-4-one 25 The product is obtained according to the process of Preparation 6, Steps A to B, using 1H-inden-3-ylacetic acid as substrate in Step A. -20- StepB: l-(lH-Inden-3-ylacetyl)-4-piperidinone oxime A mixture of 11.5 g of the product obtained in Step A, 12.5 g of hydroxylamine hydrochloride, 13.3 g of sodium acetate and 100 ml of ethanol is heated at reflux for 1 hour. The reaction mixture is then filtered, concentrated, taken up in water and extracted 5 with dichloromethane. The organic phase is then dried and evaporated, enabling the expected product to be isolated. Meltine point: 190-192°C Step C: l-[2-(lH-Inden-3-yl)ethyl]-4-piperidinamine A solution of 6.8 g of the product obtained in Step B in 123 ml of tetrahydrofiiran is added 10 at room temperature to a suspension of 4 g of lithium aluminium hydride in 12 ml of tetrahydrofiiran. After 12 hours' stirring at room temperature, hydrolysis is carried out with 2.8 ml of water, 2.2 ml of 20% sodium hydroxide solution and 10.1 ml of water, and then the reaction mixture is filtered and concentrated under reduced pressure, enabling the expected product to be isolated. 15 PREPARATION 9 ; l-[2-(5-Methoxy-l//-inden-3-yi)ethyl]-4-piperidinamine The product is obtained according to the process of Preparation 8, using (5-methoxy-l//-inden-3-yl)acetic acid as substrate in Step A. PREPARATION 10: 20 l-[2-(6-Fluoro-l//-inden-3-yl)ethyl]-4-piperidinamine The product is obtained according to the process of Preparation 8, using (6-fluoro-l//-inden-3-yl)acetic acid as substrate in Step A. -21 - PREPARATION 11 : l-[3-(Benzofuran-2-yl)propyl]-A'- methyl-4-piperidinamine Step A : 8-[3-(Benzofuran-2-yl)propyl]-l,4-dioxa-8-azaspirof4. SJdecane A solution of 5 g of 3-(benzofuran-2-yl)-l-bromopropane, 3 g of l,4-dioxa-8-azaspiro[4.5]decane and 5.8 g of potassium carbonate in 200 ml of acetone is refluxed for 24 hours, and then evaporated to dryness. The residue is taken up in ethyl acetate, washed with water, dried and evaporated to yield the expected product. Step B: l-[3-(Benzofuran-2-yl)propyl]-4-piperidinone A solution of 6 g of the product of Step A, 60 ml of 10% sulphuric acid and 30 ml of tetrahydrofiiran is heated at 50°C for 12 hours, and then evaporated. The residue is taken up in ether, rendered basic with 20% sodium hydroxide solution, extracted with ethyl acetate, dried and evaporated, enabling the expected product to be isolated. Step C: l-[3-(Benzofuran-2-yl)propyl]-N-methyl-4-piperidinamine The product is obtained according to the process of Step C of Preparation 6, using the product obtained in the preceding Step B as substrate. PREPARATION 12 : l-[3-(Benzofuran-3-yl)propyl]-4-piperidinamine The product is obtained in four steps using, in the first step, the process of Step A of Preparation 11 with 3-(benzofiiran-3-yl)-l-bromopropane as substrate, then the process of Step B of Preparation 6, and then the process of Steps C and D of Preparation 8. PREPARATION 13 : l-[(4-Methoxybenzofuran-3-yl)methyI]-4-piperidinamine -22- Stev A : Tert-butyl l-(4-methoxybenzofuran-3-carbonyI)-4-piperidylcarbamate A solution of 2.9 g of 4-methoxybenzofuran-3-ylcarboxylic acid chloride in 4 ml of dichloromethane is added, at 0°C, to a solution of 4.3 ml of diisopropylethylamine and 2.75 g of terf-butyl Ar-(4-piperidyl)carbamate in 43 ml of dichloromethane. After 12 hours' stirring at room temperature, the reaction mixture is washed with water, decanted, dried and then evaporated, enabling the expected product to be isolated. Step B: l-(4-Methoxybenzofuran-3-carbonyl)-4-piperidinamine The product is obtained according to the process of Step B of Preparation 7, using the product obtained in the preceding Step A as substrate. Step C: l-[3-(Benzofuran-3-yl)propyl]-4-piperidinamine The product is obtained according to the process of Step D of Preparation 8, using the product obtained in the preceding Step B as substrate. PREPARATION 14 : l-[(Benzofuran-3-yl)methyl]-4-piperidinamine The product is obtained according to the process of Preparation 13, Steps A to C, using benzofuran-3-ylcarboxylic acid chloride as substrate in Step A. PREPARATION 15 : l-[2-(6-Methoxy-benzofuran-3-yl)ethyl]-4-piperidinamine The product is obtained according to the process of Preparation 13, Steps A to C, using (6-methoxybenzofuran-3-yl)acetic acid as substrate in Step A. PREPARATION 16 : l-[2-(Benzofuran-3-yI)ethyI]-4-[(methylamino)methyl]-4-piperidinol -23- Step A: Ethyl N-(l-benzyl~4-hydroxy-4-piperidyl)methylcarbamate A solution of 14.75 g of ethyl chloroformate in 125 ml of dichloromethane is added, at 0°C, to a solution of 30 g of l-benzyl-4-aminomethyl-piperidin-4-ol and 13.8 g of triethylamine in 250 ml of dichloromethane. After 10 minutes' contact, the reaction 5 mixture is washed with 0.1N sodium hydroxide solution and then dried over MgSC>4. Concentration under reduced pressure enables the expected product to be isolated. Step B: Ethyl N-(4-hydroxy-4-piperidyl)methylcarbamate A solution of 47.7 g of the product obtained in Step A, 51.4 g of ammonium formate, 9.5 g of 10% palladium-on-carbon and 1600 ml of methanol is refluxed for 1 hour. After cooling 10 and filtration, concentration under reduced pressure enables the expected product to be isolated. Step C: Ethyl N-({l-[2-(benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl}-methyl)-carbamate A mixture of 15 g of 2-(benzofuran-3-yl)-l-bromoethane, 13.5 g of the product obtained in 15 Step B, 73.5 g of potassium carbamate, 21.5 g of tetrabutylammonium bromide and 150 ml of acetonitrile is stirred vigorously for 4 days at room temperature. The reaction mixture is then concentrated, taken up in ethyl acetate, washed with water, dried over MgSC>4 and then evaporated. Chromatography of the residue over silica gel (CI^Cb/EtOH/NtLjOH : 95/5/0.5) enables the expected product to be isolated. 20 Step D: l-[2-(Benzofuran-3-yl)ethyl]-4-[(methylamino)methyl]-4-piperidinol A solution of 13.4 g of the product obtained in Step C m 130 ml of tetrahydrofiiran is added, at a reaction mixture temperature of 20°C, to a suspension of 3.63 g of lithium aluminium hydride in 20 ml of tetrahydrofiiran. After 9 hours' reflux and then 12 hours at room temperature, the reaction mixture is hydrolysed, filtered and then concentrated under -24- reduced pressure, enabling the expected product to be isolated. PREPARATION 17: 4-(Aminomethyl)-l-[2-(benzofuraii-3-yl)ethyl]-4-piperidinol A solution of 2 g of the product obtained in Step C of Preparation 16, 0.65 g of potassium hydroxide, 23 ml of ethanol and 17 ml of water is brought to reflux. After 24 hours, 0.65 g of potassium hydroxide is added and refluxing is maintained for 3 days. The reaction mixture is then concentrated, and subsequently diluted with dichloromethane, washed with water, neutralised, dried and then concentrated under reduced pressure, enabling the expected product to be isolated. Melting point: 78°C preparation 18 : l-[2-(5-Fluoro-benzofuran-3-yl)ethyl]-4-[(methylamino)methyI]-4-piperidinol The product is obtained according to the process of Preparation 16, Steps A to D, using 2-(5-fluoro-benzofuran-3-yl)-l-bromoethane in Step C. preparation 19 : 4-(Aminomethyl)-l-[2-(5-fluoro-benzofuran-3-yl)ethyl]-4-piperidinol The product is obtained according to the process of Preparation 17, using ethyl N-{l-[2-(5-fluoro-benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidylmethyl}carbamate as substrate, which is prepared as for the product of Step C of Preparation 16 starting from 2-(5-fluoro-benzofuran-3-yl)-1 -bromoethane. preparation 20 : l-[2-(7-Methoxy-benzofuran-3-yI)ethyl]-4-[(methylamino)methyl]-4-piperidinol The product is obtained according to the process of Preparation 16, Steps A to D, using 2-(7-methoxy-benzofuran-3-yl)-l-bromoethane in Step C. -25- PREPARATION 21 : 4-(Aminomethyl)-l-[2-(5-methoxy-beiizofuraii-3-yI)ethyl]-4-piperidinol The product is obtained according to the process of Preparation 17, using ethyl N-({l-[2-(5 -methoxy-benzofuran-3 -yl)ethyl] -4-hydroxy-4-piperidyl} methyl)carbamate as substrate, which is prepared according to the process of Preparation 16, Steps A to C, using 2-(5-methyloxy-benzofuran-3-yl)-l-bromoethane in Step C. PREPARATION 22: 4-(Aminomethyl)-l-[2-(l//-inden-3-yl)ethyl]-4-piperidinol The product is obtained according to the process of Preparation 17, using ethyl N-({l-[2-(1 //-inden-3-yl)ethyl]-4-hydroxy-4-piperidyl} methyl)carbamate as substrate, which is prepared according to the process of Preparation 16, Steps A to C, using 2-(l//-inden-3-yl)-l-bromoethane in Step C. PREPARATION 23 : l-[2-(5-Methoxy-benzofuran-3-yl)ethyl]-4-[(methylamino)methyl]-4-piperidinol The product is obtained according to the process of Preparation 16, Steps A to D, using 2-(5-methoxy-benzofuran-3-yl)-l -bromoethane as substrate in Step C. PREPARATION 24: 4-(Aminomethyl)-l-[2-(7-methoxy-benzofuran-3-yI)ethyl]-4-piperidinol The product is obtained according to the process of Preparation 17, using the product obtained in Step C of Preparation 20 as substrate. PREPARATION 25 : l-[2-(l//-Inden-3-yl)ethyl]-4-[(methylamino)methyl]-4-piperidinol -26- The product is obtained according to the process of Preparation 16, Steps A to D, using 2-(l//-inden-3-yl)-l -bromoethane as substrate in Step C. preparation 26 : 4-(2-Aminoethyl)-l-[2-(ben2ofuraii-3-yI)ethyl]-4-piperidinol The product is obtained according to the process of Preparation 16, Steps A to D, using 4-(2-aminoethyl)-l-benzyl-4-piperidinol as substrate in Step A, and then subjecting the product to the process of Preparation 17. preparation 27: 1-[2-(5-Hydroxy-benzofuran-3-yl)ethyl]-4-[(methylamino)methyl]-4-piperidinol 6.46 ml of a 1M solution of boron tribromide in dichloromethane are added, at a temperature of from -5 to -10°C, to a solution of 3.23 mmol of the product of Preparation 23 in 14.3 ml of chloroform. After 12 hours' reaction at room temperature, the reaction mixture is hydrolysed and rendered basic with powdered sodium hydrogen carbonate. The expected product is isolated by extraction and purification. preparation 28 : 2-(4-Amino-l-piperidyl)-l-(benzofuran-3-yl)-ethanol Step A : Tert-butyl l-[2-(benzofuran-S-yl)-2-oxoethyl]-4-piperidylcarbamate 10 g of l-(benzofuran-3-yl)-2-bromoethanone are added to a suspension of 8.4 g of tert-butyl Ar-(piperid-4-yl)carbamate, 17.3 g of potassium carbonate and 80 ml of acetonitrile. After 1 hour 45 minutes' reaction at room temperature, the reaction mixture is diluted with water, extracted with ethyl acetate, and then dried over MgSC>4 and concentrated under reduced pressure, enabling the expected product to be obtained. Step B : Tert-butyl l-/2-(benzofuran-3-yl)-2-hydroxyethylJ-4-piperidylcarbamate -27- 1.2 g of sodium borohydride are added in portions to a solution of 7.7 g of the product obtained in Step A in 100 ml of ethanol. After 1 hour's reaction, the solution is evaporated, taken up in water, extracted with ethyl acetate, dried and then concentrated under reduced pressure. Chromatography over silica gel (dichloromethane/ethanol : 95/5) enables the expected product to be isolated. Step C: 2-(4-Amino-l-piperidyl)-l-(benzofuran-3-yl)-ethanol The product is obtained according to the process of Preparation 7, using the product obtained in the preceding Step B as substrate. preparation 29: l-(4-Amino-l-piperidyl)-3-(benzofuran-3-yl)-2-propanol Step A : Tert-butyl l-[3-(benzofuran-3-yl)-2-hydroxypropylJ-4-piperidyl-carbamate A solution of 2.9 g of 3-(2-oxiranylmethyl)benzofuran, 4 g of tert-butyl 4-piperidyl-carbamate and 35 ml of isopropanol is heated at 80°C for 5 hours After evaporation to dryness, chromatography over silica gel enables the expected product to be isolated. Meltine point (K.) : 118-120°C Step B: l-(4-Amino-l-piperidyl)-3-(benzofuran-3-yl)-2-propanol The product is obtained according to Step B of Preparation 7, using the product of the preceding Step A as substrate. preparation 30 : l-[3-(Benzofuran-3-yl)-2-fluoropropyl]-4-piperidinamine Step A : Tert-butyl l-[3-(benzofuran-3-yl)-2-fluoropropyl]-4-piperidylcarbamate A solution of 0.85 ml of diethylaminosulphur trifluoride in 10 ml of dichloromethane is -28- added dropwise, under argon and at 0°C, to a solution of 2 g of the product obtained in Step A of Preparation 29 in 25 ml of dichloromethane. After 2 hours' reaction at 0°C and 1 hour at room temperature, the reaction mixture is hydrolysed at 0°C with an aqueous 10% NaHCC>3 solution. After decanting, drying and evaporation, chromatography over 5 silica gel (dichloromethane/ethanol: 95/5) enables the expected product to be isolated. Meltine point: 118-120°C Step B: l-[3-(Benzofuran-3-yl)-2-fluoropropyl]-4-piperidinamine A stream of hydrogen chloride gas is circulated through a solution of 3.64 g of the product obtained in Step A in 70 ml of ethanol. After 2 hours' stirring at 50°C, the reaction mixture 10 is concentrated under reduced pressure. The residue is taken up in water and in 20% sodium hydroxide solution, extracted with dichloromethane, dried and then evaporated, enabling the expected product to be isolated. PREPARATION 31 : l-[2-(Benzofuran-3-y])-l-(fluoromethyl)ethyl]-4-piperidinamine 15 The product is obtained according to the process of Step B of Preparation 30 using as substrate the first product isolated in the course of the chromatography over silica gel carried out in Step A of Preparation 30. PREPARATION 32 : 20 7-Methoxy-li/-pyrrolo[2,3-c]pyridine-3-sulphonyl chloride Step A : (2-Methoxy-3-nitro-4-pyridyl)acetonitrile A solution, cooled to -30°C, of 68.8 g of potassium tert-butylate in 250 ml of dimethylformamide is added, at a temperature less then -15°C and over a period of 45 minutes, to a solution of 40 g of 2-methoxy-3-nitropyridine and 48.8 g of 4-25 chlorophenoxyacetonitrile in 350 ml of dimethylformamide. After 1 hour 30 minutes' reaction at a temperature of from -20 to -10°C, the reaction mixture is poured into 2 litres -29- of IN hydrochloric acid and then the solution is stirred for 30 minutes at -10°C. The resulting precipitate is filtered off, dried and recrystallised from anhydrous ethanol, enabling the expected product to be isolated. Meltine point (K.) : 110-114°C Step B : 7-Methoxy-lH-pyrrolof2,3-cJpyridine 3.1 g of 10% Pd/C are added to a solution of 30.8 g of the product obtained in Step A in 600 ml of anhydrous ethanol and 150 ml of acetic acid. The mixture is hydrogenated at room temperature, under 4 bars, for 6 hours and is then filtered and concentrated under reduced pressure. The residue is taken up in 50 ml of a saturated sodium hydrogen carbonate solution, diluted with ethyl acetate, brought to pH = 8 by the addition of sodium hydrogen carbonate, decanted, washed with water, dried and then concentrated under reduced pressure, enabling the expected product to be obtained. Meltine point (K.) : 129-132°C Step C: 3-Bromo-7-methoxy-lH-pyrrolo[2,3-c]pyridine 19.7 g of N-bromosuccinimide are added, over the course of 5 minutes, to a solution of 16.5 g of the product obtained in Step B in 340 ml of anhydrous ethanol. After 12 hours' stirring at room temperature, the reaction mixture is concentrated in vacuo, taken up in water and in ether, washed, dried and concentrated. Chromatography over silica gel (dichloromethane/cyclohexane : 80/20 to 100/0) enables the expected product to be isolated. Meltine point (K.) : 130-134°C Step D: 3-Bromo-l-(tert-butyldimethyl)silyl- 7-methoxy-lH-pyrrolo[2,3-c]-pyridine 22.7 ml of a 1.6M w-butyllithium solution in tetrahydrofiiran are added to a solution, cooled to -76°C, of 7.5 g of the product obtained in Step C in 200 ml of tetrahydrofiiran. After 20 minutes' stirring at that temperature, 5.5 g of tert-butyldimethylsilyl chloride in -30- 50 ml of tetrahydrofiiran are added, and stirring is maintained for 3 hours at -76°C. After returning to room temperature, 15 ml of water, 200 ml of a saturated sodium chloride solution and 600 ml of ether are added. The solution is decanted, dried and then concentrated under reduced pressure. Chromatography over silica gel (dichloromethane : 5 100 %) enables the expected product to be isolated. Step E: 7-Methoxy-lH-pyrrolo[2,3-c]pyridine-3-sulphonyl chloride 11 ml of /err-butyllithium are added to a solution, cooled to -80°C, of 3 g of the product obtained in Step D in 80 ml of ether. After 30 minutes' stirring at that temperature, a stream of sulphur dioxide is passed through the reaction mixture for 10 minutes, and then 2.3 g of 10 N-chlorosuccinimide in 40 ml of tetrahydrofiiran are added, and the reaction mixture is returned to room temperature. The expected product is isolated by concentration under reduced pressure and purification of the residue. PREPARATION 33 : 15 4-Bromo-5-isoquinolinesulphonyl chloride hydrochloride Step 1:4-Bromo-S-nitro-isoquinoline Add 11 g of 4-bromoisoquinoline to 45 ml of sulphuric acid, followed, dropwise, by a solution of 9.1 g of potassium nitrate in 45 ml of sulphuric acid whilst cooling in an ice-bath. The reaction mixture is stirred at room temperature for 2 hours 30, before being 20 poured onto ice. After the resulting solution has been rendered basic with ammonium hydroxide, the crystals are filtered off, washed and dried to yield the expected product. Meltine point (K) : 176-178°C Step 2: S-Amino-4-bromoisoquinoline 100 ml of concentrated hydrochloric acid are added to a suspension of 16 g of the 25 compound obtained in Step 1 in 55 ml of ethanol. The mixture is cooled with ice and stirred whilst a solution of 62.6 g of SnCl2.2H20 in 100 ml of ethanol is being introduced -31 - and then for a further 3 hours. After removal of the solvent by evaporation, the residue is diluted with 140 ml of ice-cold water and rendered basic with 2N sodium hydroxide solution. The resulting aqueous phase is extracted 3 times with 350 ml of methylene chloride each time. The combined organic phases are dried over MgSC>4 and evaporated. 5 The residue is purified by flash chromatography (CthCh/MeOH : 98/2) to yield the expected product. Meltine point (K) ; 151-153°C Step 3 :4-Bromo-5-isoquinolinesulphonyl chloride A solution of 3.45 g of sodium nitrite in 14 ml of water is added dropwise, at -5°C, to a 10 suspension of 5.4 g of the product obtained in Step 2 in 66 ml of concentrated hydrochloric acid, and the solution is stirred for 30 minutes at room temperature (solution A). There is prepared, separately, an aqueous solution (8.5 ml) of 1.95 g of CUCI2.2H2O, which is introduced into 42 ml of a solution of acetic acid saturated with sulphurous anhydride. The resulting solution is poured dropwise into solution A, and then the reaction mixture is 15 stirred for one hour at room temperature before being warmed at 30°C for 30 minutes in a water bath. The expected product is isolated by extraction with chloroform, decanting, washing with a saturated solution of sodium hydrogen carbonate and customary treatment. Meltine point (K) : 84-86°C 20 PREPARATION 34: 4-Fluoro-5-isoquinolinesulphonyl chloride The product is obtained according to the process of Preparation 33, Steps 1 to 3, but in Step 1 of that Preparation using 4-fluoroisoquinoline, the preparation of which is described in J. Am. Chem. Soc., 1951, pp. 687-688, instead of 4-bromoisoquinoline. 25 Meltine point (K) : 88-89°C example i : A-({l-[2-(Benzofuran-3-yl)ethyl)-4-piperidyl}methyl)-Ar-niethyl-5-isoquinoline-sulphonamide and its dihydrochloride -32- 5.1 g of 5-isoquinolinesulphonyl chloride hydrochloride is added in fractions to a solution, cooled to 0°C, of 5.26 g of the product of Preparation 1 and 5.5 g of diisopropylethylamine in 750 ml of dichloromethane. After 6 hours' reaction at room temperature, the mixture is concentrated under reduced pressure, taken up in ethyl acetate, washed with water, dried and evaporated. Chromatography over silica gel (dichloromethane/methanol : 95/5) enables the expected product to be isolated, which is converted to the dihydrochloride with a solution of ethereal hydrogen chloride. Meltine point: 237-239°C Elemental microanalysis: C H N CI S % found 57.77 5.79 7.99 13.68 5.65 % calculated 58.21 5.82 7.83 13.22 5.98 EXAMPLE 2 : 2-Acetyl-8-chloro-/V-({l-[2-(benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-iV-methyl-1^3>4-tetrahydro-5-isoquinolinesulphonamide and its fumarate The product is obtained according to the process of Example 1, using 2-acetyl-8-chloro-l,2,3,4-tetrahydro-5-isoquinolinesulphonyl chloride as reagent. The resulting product is converted to its fumarate with a solution of 0.172M fumaric acid in ethanol. Meltine point (M.K.) : 168-170°C Elemental microanalysis: C H N CI S % found 57.77 5.86 6.21 5.35 4.36 % calculated 58.22 5.80 6.36 5.37 4.86 EXAMPLE3; 7V-({l-[2-(Benzofuran-2-yI)ethyl]-4-piperidyl}methyl)-A-methyl-5-isoquinoIine-sulphonamide The product is obtained according to the process of Example 1 using the compound of Preparation 2 as substrate instead of the compound of Preparation 1. Meltine point (M.K.) : 105-108°C -33- Elemental microanalysis: % found % calculated C H 67.48 6.47 67.36 6.30 N S 9.14 6.68 9.06 6.92 7V-({l-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-5-isoquinolinesulphonamide and its fumarate The product is obtained according to the process of Example 1 using the compound of Preparation 3 as substrate instead of the compound of Preparation 1. The resulting product is converted to its fumarate. Meltine point (M.K.) : 140-155°C Elemental microanalysis: C H N S % found 61.29 5.63 7.27 5.31 % calculated 61.58 5.52 7.43 5.67 7V-({l-[2-(l//-Inden-3-yl)ethyI]-4-piperidyl}methyl)-7V-methyl-5-isoquinoline-sulphonamide The product is obtained according to the process of Example 1 using the compound of Preparation 4 as substrate instead of the compound of Preparation 1. The product is crystallised from isopropyl ether. Meltine point (M.K.) : 92-95°C Elemental microanalysis: C H N S % found 70.30 6.70 9.17 6.45 % calculated 70.25 6.77 9.10 6.95 -34- ex ample 6 : iV-({l-[(2 E)-3-(Benzofuran-2-yl)-2-propenyI]-4-piperidyI}methyl)-A-methyl-5-isoquinolinesulphonamide The product is obtained according to the process of Example 1 using the compound of Preparation 5 as substrate instead of the compound of Preparation 1. The product recrystallises from acetonitrile. Meltine point (K.) : 109°C Elemental microanalysis : C H N S % found 68.57 6.23 8.95 6.57 % calculated 68.19 6.15 8.83 6.74 example 7: A?-{l-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-/V-methyl-5-isoquinolinesuIphonamide and its hemifumarate The product is obtained according to the process of Example 1 using the compound of Preparation 6 as substrate instead of the compound of Preparation 1. The product is converted to its hemifumarate, which recrystallises from ethyl acetate. Meltine point (M.K.) : 122-124°C Elemental microanalysis: C H N S % found 63.30 5.71 8.00 6.43 % calculated 63.88 5.77 8.29 6.32 example 8: A-{l-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-5-isoquinolinesulphonamide and its fumarate The product is obtained according to the process of Example 1 using the compound of Preparation 7 as substrate instead of the compound of Preparation 1. The product is converted to its fumarate. Meltine point (M.K.) : 230-235°C -35- Elemental microanalysis: C H N S % found 60.90 5.17 7.50 6.08 % calculated 60.97 5.30 7.62 5.81 example 9: Ar-{l-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-2,13-benzoxadiazole-4-sulphonamide and its fumarate 3.13 g of benzo[2,l,3]oxadiazole-4-sulphonic acid chloride are added to a solution, at 0°C, of 3.5 g of the product of Preparation 7 and 1.85 g of diisopropylethylamine in 35 ml of dichloromethane. After 3 hours at room temperature, the reaction mixture is washed with water, dried and evaporated. The residue is taken up in a 0.172M solution of fumaric acid in ethanol. The resulting precipitate is filtered off. It recrystallises from ethanol to yield the expected product. Meltine point (M.K.) : 200-210°C Elemental microanalysis: C H N S % found 55.00 4.96 10.15 6.19 % calculated 55.34 4.83 10.33 5.91 example 10 : A,-{l-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-l-naphthylsulphonamide and its fumarate The product is obtained according to the process of Example 8 using naphthalene-1-sulphonyl chloride as reagent instead of 5-isoquinolinesulphonyl chloride. The product is converted to its fumarate. Meltine point (M.K.) : 226-230°C Elemental microanalysis: C H N S % found 63.04 5.50 5.10 5.67 % calculated 63.26 5.49 5.09 5.82 -36- EXAMPLE 11: iV-{l-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-5-chloronaphthyl-l-sulphonamide The product is obtained according to the process of Example 8 using 5-chloro-naphthalene-1-sulphonyl chloride as reagent instead of 5-isoquinolinesulphonyl chloride. Meltine point (M.K.) : 107-110°C Elemental microanalysis : C H N S CI % found 64.16 5.38 6.15 6.72 7.49 % calculated 64.02 5.37 5.97 6.84 7.48 EXAMPLE 12 : A'-{l-[2-(Benzofuran-3-yl)ethyl]-4-piperidyI}-7-methoxynaphthyl-l-sulphonamide The product is obtained according to the process of Example 8 using 7-methoxynaphthalene-1-sulphonyl chloride as reagent instead of 5-isoquinolinesulphonyl chloride. The product crystallises from a mixture of ether/heptane. Meltine point (M.K.) ; 140-145°C Elemental microanalysis: C H N S % found 66.99 6.24 5.92 6.73 % calculated 67.22 6.07 6.03 6.90 EXAMPLE 13 : 7V-{l-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-7-chlorofuro[23-c]pyridine-3-sulphonamide and its fumarate The product is obtained according to the process of Example 8 using 7-chlorofuro[2,3-c]pyridine-3-sulphonyl chloride as reagent instead of 5-isoquinolinesulphonyl chloride. The product is converted to its fumarate. Meltine point (M.K.) : 185-195°C -37- Elemental microanalysis: C H N CI S % found 54.94 4.82 7.70 6.52 5.90 % calculated 55.04 4.62 7.76 6.55 5.92 EXAMPLE 14 : l-Chloro-iV-{l-[2-(benzofuran-3-yl)ethyl]-4-piperidyl}-5-isoquinolinesulphonamide The product is obtained according to the process of Example 8 using 1-chloro-isoquinoline-5-sulphonyl chloride as reagent instead of 5-isoquinolinesulphonyl chloride. Meltine point (M.K.) : 130-132°C Elemental microanalysis: C H N CI S % found 61.44 5.19 9.00 7.57 6.69 % calculated 61.33 5.15 8.94 7.54 6.82 EXAMPLE 15: /V-{l-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-7-chlorothieno[23-c]pyridine-3-sulphonamide and its fumarate The product is obtained according to the process of Example 8 using 7-chlorothieno[2,3-c]pyridine-3-sulphonyl chloride as reagent instead of 5-isoquinolinesulphonyl chloride. Meltine point (M.K.) : 170-173°C Elemental microanalysis: C H N CI S % found 52.58 4.41 6.97 6.21 11.13 % calculated 52.74 4.43 7.10 5.99 10.83 EXAMPLE 16 : l-Ethoxy-A-{l-[2-(benzofuran-3-yl)ethyl]-4-piperidyl}-5-isoquinolinesulphonamide The product is obtained according to the process of Example 8 using l-ethoxy-5-isoquinolinesulphonyl chloride as reagent instead of 5-isoquinolinesulphonyl chloride. -38- Meltine point (M.K.) : 109-114°C Elemental microanalysis: C H N S % found 65.10 6.35 8.66 6.72 % calculated 65.11 6.09 8.76 6.69 EXAMPLE 17: l-Methoxy-/V-{l-[2-(benzofuran-3-yl)ethyl]-4-piperidyl}-5-isoquinolinesulphonainide The product is obtained according to the process of Example 8 using l-methoxy-5-isoquinolinesulphonyl chloride as reagent instead of 5-isoquinolinesulphonyl chloride. Meltine point (M.K.) : 124-128°C Elemental microanalysis: C H N S % found 64.43 6.03 9.07 6.99 % calculated 64.50 5.85 9.03 6.89 EXAMPLE 18 : A-{l-|2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-5-chloro-13-dimethyl-l-//-pyrazole-4-sulphonamide and its hydrochloride The product is obtained according to the process of Example 8 using 5-chloro-l,3-dimethyl-1 #-pyrazole-4-sulphonyl chloride as reagent instead of 5-isoquinolinesulphonyl chloride. Meltine point (M.K.) : 205-210°C Elemental microanalysis: C H N CI S % found 50.57 5.61 11.50 15.40 6.95 % calculated 50.74 5.54 11.83 14.98 6.77 EXAMPLE 19 : A-{l-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-3,5-dimethyI-4-isoxazolesuIphonamide and its hydrochloride -39- The product is obtained according to the process of Example 8 using 3,5-dimethyl-4-isoxazolesulphonyl chloride as reagent instead of 5-isoquinolinesulphonyl chloride. Meltine point (M.K.) : 266-268°C Elemental microanalysis: C H N CI S % found 54.59 6.06 9.31 8.28 7.55 % calculated 54.60 5.96 9.55 8.06 7.29 EXAMPLE 20 : JV-{l-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-7-oxo-6,7-dihydro-l//-pyrrolo- [23-c]pyridine-3-sulphonamide The product is obtained according to the process of Example 8 using the product of Preparation 32 as reagent instead of 5-isoquinolinesulphonyl chloride. Meltine point (M.K.) : 251-255°C Elemental microanalysis: C H N S % found 59.70 5.44 12.41 7.18 % calculated 59.98 5.49 12.72 7.28 EXAMPLE 21 : A-{l-[2-(l/f-Inden-3-yl)ethyl]-4-piperidyl}-5-isoquinolinesulphonamide The product is obtained according to the process of Example 1 using the compound of Preparation 8 as substrate instead of the compound of Preparation 1. Meltine point (M.K.) : 170-172°C Elemental microanalysis: C H N S % found 69.28 6.32 9.68 7.45 % calculated 69.26 6.28 9.69 7.40 -40- fx ample 22 : _/V-{l-[2-(5-Methoxy-l//-inden-3-yl)ethyl]-4-piperidyl}-5-isoquinoIinesulphonamide and its fumarate The product is obtained according to the process of Example 1 using the compound of Preparation 9 as substrate instead of the compound of Preparation 1. Meltine point (M.K.) : 165-170°C Elemental microanalysis: C H N S % found 61.93 5.75 7.10 5.53 % calculated 62.16 5.74 7.25 5.53 example 23 : A-{l-[2-(7-Fluoro-l//-inden-3-yl)ethyl]-4-piperidvl}-5-isoquinolinesulphonamide and its fumarate The product is obtained according to the process of Example 1 using the compound of Preparation 10 as substrate instead of the compound of Preparation 1. Meltine point (M.K.) : 215-222°C Elemental microanalysis: C H N S % found 61.36 5.43 7.18 5.61 % calculated 61.36 5.33 7.40 5.65 example 24 : N-{l-[3-(Benzofuran-2-yI)propyl]-4-piperidyl}-N-methyl-5-isoquinoline-suiphonamide and its fumarate The product is obtained according to the process of Example 1 using the compound of Preparation 11 as substrate instead of the compound of Preparation 1. Meltine point (M.K.) : 146-148°C -41 - Elemental microanalysis: C H N S % found 62.23 5.86 6.99 5.23 % calculated 62.16 5.74 7.25 5.53 EXAMPLE 25 : N-{ 1- [3-(Benzofuran-3-y l)propy I] -4-piperidy 1} -5-isoquinolinesulphonamide The product is obtained according to the process of Example 1 using the compound of Preparation 12 as substrate instead of the compound of Preparation 1. Meltine point (M.K.) : 115-118°C Elemental microanalysis: C H N S % found 66.79 6.05 9.35 7.13 % calculated 66.20 6.27 9.28 6.91 EXAMPLE 26: 7V-{l-[(4-Methoxy-benzofuran-3-yl)methyl]-4-piperidyl}-5-isoquinolinesulphonamide and its hemifumarate The product is obtained according to the process of Example 1 using the compound of Preparation 13 as substrate instead of the compound of Preparation 1. Meltine point (M.K.) : 204-219°C Elemental microanalysis: C H N S % found 60.82 5.44 7.95 6.00 % calculated 61.28 5.35 8.25 6.29 EXAMPLE 27 : jV-{l-[(Benzofuran-3-yl)methyl]-4-piperidyl}-5-isoquinolinesulphonamide and its fumarate The product is obtained according to the process of Example 1 using the compound of Preparation 14 as substrate instead of the compound of Preparation 1. -42- Meltine point (M.K.): 203-208°C Elemental microanalysis: C H N S % found 59.40 5.12 7.80 5.48 % calculated 59.54 5.10 7.49 5.72 EXAMPLE 28: yV-{l-[2-(6-Methoxy-beiizofuran-3-\i)ethyl]-4-piperidyl}-5-isoquinolinesulphonamide and its fumarate The product is obtained according to the process of Example 1 using the compound of Preparation 15 as substrate instead of the compound of Preparation 1. Meltine point (M.K.) : 174-178°C Elemental microanalysis: C H N S % found 59.64 5.55 7.16 5.32 % calculated 59.89 5.37 7.22 5.51 EXAMPLE 29 : l-Methoxy-AT-{l-[2-(6-methoxy-benzofuran-3-yl)ethyl]-4-piperidyl}-5-isoquinolinesulphonamide and its fumarate The product is obtained according to the process of Example 1 using the compound of Preparation 15 as substrate instead of the compound of Preparation 1, and using 1-chloroisoquinoline-5-sulphonyl chloride as reagent. The product, obtained by chromatography over silica gel, is treated with methanolic potassium hydroxide to yield the expected product. Meltine point (M.K.) : 194-196°C Elemental microanalysis: C H N S % found 58.99 5.54 6.95 5.08 % calculated 58.91 5.44 6.87 5.24 -43- EXAMPLE 30 : Ar-({l-[2-(Benzofuran-3-vl)ethyl]-4-hydroxy-4-piperidyI}methyl)-Ar-methyl-5-isoquinolinesulphonamide The product is obtained according to the process of Example 1 using the compound of Preparation 16 as substrate instead of the compound of Preparation 1. Meltine point (M.K.) : 115-120°C Elemental microanalysis: C H N S % found 64.76 6.03 8.60 6.85 % calculated 65.11 6.09 8.76 6.69 EXAMPLE 31 : 7V-({l-[2-(Benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl}methyI)-jV-methyi-2,13-benzothiadiazole-4-sulphonamide and its hydrochloride The product is obtained according to the process of Example 1 using the compound of Preparation 16 as substrate instead of the compound of Preparation 1, and using 2,1,3-benzothiadiazole-4-sulphonyl chloride as reagent. Meltine point (M.K.) : 217-220°C Elemental microanalysis: C H N CI S % found 53.10 5.41 10.64 6.80 12.37 % calculated 52.81 5.20 10.71 6.78 12.26 EXAMPLE 32: Ar-({l-[2-(Benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl}methyl)-A-methyl-2,lr3- benzoxadiazole-4-sulphonamide and its fumarate The product is obtained according to the process of Example 1 using the compound of Preparation 16 as substrate instead of the compound of Preparation 1, and using 2,1,3-benzoxadiazole-4-sulphonyl chloride as reagent. -44- Meltine point (M.K.) : 216-223°C Elemental microanalysis: C H N S % found 55.38 5.31 9.60 5.30 % calculated 55.28 5.15 9.55 5.47 EXAMPLE 33: N-({1 -[2-(Benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl} methyI)-5-isoquinolinesulphonamide The product is obtained according to the process of Example 1 using the compound of Preparation 17 as substrate instead of the compound of Preparation 1. Meltine point (M.K.) : 120-130°C Elemental microanalysis : C H N S % found 64.68 5.82 9.00 6.47 % calculated 64.50 5.85 9.03 6.89 EXAMPLE 34 : ./V-({l-[2-(Benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl}methyl)-2,13- benzoxadiazole-4-sulphonamide The product is obtained according to the process of Example 1 using the compound of Preparation 17 as substrate instead of the compound of Preparation 1, and using 2,1,3-benzoxadiazole-4-sulphonyl chloride as reagent. Meltine point (M.K.) : 140-142°C Elemental microanalysis: C H N S % found 58.11 5.36 12.09 6.87 % calculated 57.88 5.30 12.27 7.02 EXAMPLE 35 : 7V-({l-[2-(5-Fluoro-benzofuran-3-yl)ethyI]-4-hydroxy-4-piperidvl}methyl)-A-methyl-5-isoquinolinesulphonamide and its dihydrochloride -45- The product is obtained according to the process of Example 1 using the compound of Preparation 18 as substrate instead of the compound of Preparation 1. Meltine point (M.K.) : 195-200°C Elemental microanalysis : C H N CI S % found 55.12 5.34 7.31 12.42 5.61 % calculated 54.74 5.30 7.37 12.43 5.62 EXAMPLE 36 : A'r-({l-[2-(5-Fluoro-benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl}methyl)-S-isoquinolinesulphonamide and its dihydrochloride The process is obtained according to the process of Example 1 using the compound of Preparation 19 as substrate instead of the compound of Preparation 1. Meltine point (M.K.) : 220-230°C Elemental microanalysis: C H N CI S % found 53.50 5.14 7.49 12.79 5.92 % calculated 53.96 5.07 7.55 12.74 5.76 EXAMPLE 37 : Ar-({l-[2-(7-Methoxy-benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl}methyI)-A'-methyl-5-isoquinolinesulphonamide The product is obtained according to the process of Example 1 using the compound of Preparation 20 as substrate instead of the compound of Preparation 1. Meltine point (M.K.) : 125-135°C Elemental microanalysis: C H N S % found 63.63 6.36 8.00 6.69 % calculated 63.63 6.13 8.2S 6.29 -46- EXAMPLE 38 : 7V-({1 - [2-(7-Methoxy-benzofuran-3-y l)ethyl] -4-hy droxy-4-piperidy 1} methyl)-iV-methyl-2,13-benzoxadiazole-4-suiphonamide and its hemifumarate The product is obtained according to the process of Example 1 using the compound of Preparation 20 as substrate instead of the compound of Preparation 1, and using 2,1,3-benzoxadiazole-4-sulphonyl chloride as reagent. Meltine point (M.K.) : 175-178°C Elemental microanalysis: C H N S % found 55.73 5.43 9.96 5.79 % calculated 55.90 5.41 10.03 5.74 EXAMPLE 39: Ar-({l-[2-(5-Methoxy-benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl}methyl)-5-isoquinoiinesulphonamide The product is obtained according to the process of Example 1 using the compoimd of Preparation 21 as substrate instead of the compound of Preparation 1. Meltine point (M.K.) : 95-105°C EXAMPLE 40 : A7-({l-[2-(5-Methoxy-benzofuran-3-yl)ethylJ-4-hydroxy-4-piperidyl}methyl)-2,13-benzoxadiazole-4-sulphonamide and its fumarate The product is obtained according to the process of Example 9 using the compound of Preparation 21 as substrate instead of the compound of Preparation 1. Meltine point (M.K.) : 204-208°C Elemental microanalysis: C H N S % found 54.04 5.15 9.02 5.14 % calculated 53.81 5.02 9.30 5.32 -47- EX AMPLE 41 : 7V-({l-[2-(i//-Inden-3-yl)ethyl]-4-hydroxy-4-piperidyl}methyl)-5-isoquinoline-sulphonamide and its sesquifumarate The product is obtained according to the process of Example 1 using the compound of Preparation 22 as substrate instead of the compound of Preparation 1. Meltine point (M.K.) : 200-210°C Elemental microanalysis: C H N S % found 59.92 5.74 6.53 4.81 % calculated 60.27 5.53 6.59 5.03 EXAMPLE 42 : iY-({l-[2-(5-Methoxy-benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl}methyl)-A-methyl-5-isoquinolinesulphonamide and its fumarate The product is obtained according to the process of Example 1 using the compound of Preparation 23 as substrate instead of the compound of Preparation 1. Meltine point (M.K.) : 160-165°C Elemental microanalysis: C H N S % found 59.23 5.67 6.65 4.86 % calculated 59.51 5.64 6.72 5.12 EXAMPLE 43 : Ar-({l-[2-(7-Methoxy-benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidvl}methyl)-5-isoquinolinesulphonamide and its hemifumarate The product is obtained according to the process of Example 1 using the compound of Preparation 24 as substrate instead of the compound of Preparation 1. Meltine point (M.K.) : 160-165°C -48- Elemental microanalysis: C H N S % found 60.97 5.68 7.54 5.79 % calculated 60.75 5.64 7.59 5.79 EXAMPLE 44 : AA-({l-[2-(7i/-Inden-3-yl)ethyl]-4-hydroxy-4-piperidyl}methyl)-A-methyl-5-isoquinolinesulphonamide The product is obtained according to the process of Example 1 using the compound of Preparation 25 as substrate instead of the compound of Preparation 1. Meltins point (M.K.) : 160-162°C Elemental microanalysis: C H N S % found 67.99 6.61 8.70 6.68 % calculated 67.90 6.54 8.80 6.71 EXAMPLE 45 : Ar-({2-[2-(Benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl}ethyl)-5-isoquinoline-sulphonamide The product is obtained according to the process of Example 1 using the compound of Preparation 26 as substrate instead of the compound of Preparation 1. Meltins point (M.K.) : 174-176°C Elemental microanalysis: C H N S % found 65.09 6.19 8.81 6.55 % calculated 65.11 6.10 8.76 6.49 EXAMPLE 46 : N-({l-[2-(5-Hydroxy-benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl}niethyl)-Af-methyl-5-isoquinolinesuIphonamide and its potassium salt -49- 6.46 ml of a molar solution of boron tribromide in dichloromethane are added dropwise at -15°C to a solution of 1.65 g of the product of Example 42 in 14 ml of chloroform. After 12 hours at room temperature, the reaction mixture is hydrolysed and rendered basic with sodium hydrogen carbonate. The precipitate that forms is filtered off and then chromatographed over silica gel (dichloromethane/EtOH/NHtOH : 90/10/1). The expected product is thus isolated and converted to its potassium salt with methanolic potassium hydroxide. Meltine point (M.K.) : 185-190°C Elemental microanalysis: C H N S % found 58.03 5.20 7.06 5.52 % calculated 58.51 5.29 7.87 6.01 EXAMPLE 47 : 7V-{l-[2-(Benzofuran-3-yl)-2-hydroxyethyl]-4-piperidyl}-5-isoquinolinesulphonamide The product is obtained according to the process of Example 1 using the compound of Preparation 28 as substrate instead of the compound of Preparation 1. Meltine point (M.K.) : 160-16S°C Elemental microanalysis: C H N S % found 63.46 5.65 9.20 7.21 % calculated 63.84 5.58 9.31 7.10 EXAMPLE 48 : 7V-{l-[3-(Benzofuran-3-yl)-2-hydroxypropyl]-4-piperidyl}-5-isoquinoline-sulphonamide and its fumarate The product is obtained according to the process of Example 1 using the compound of Preparation 29 as substrate instead of the compound of Preparation 1. Meltine point (M.K.) : 102-109°C -50- Elemental microanalysis: C H N S % found 58.94 5.42 6.62 5.06 % calculated 59.24 5.32 6.98 5.32 5 EXAMPLE 49: Ar-{l-[3-(Benzofuran-3-yl)-2-hydroxypropyI]-4-piperidyl}-2-(3-pyridyl)-benzenesulphonamide and its fumarate Step A: N-{l-[3-(Benzofuran-3-yl)-2-hydroxypropyl]-4-piperidyl}-2-bromobenzenesulphonamide 10 The product is obtained according to the process of Example 1 using the compound of Preparation 29 as substrate instead of the compound of Preparation 1, and using 2-bromobenzenesulphonic acid chloride as reagent. Meltins point (M.K.) : 108-110°C Step B: N-fl-/.3-(Benzofuran-3-yl)-2-hydroxypropylJ-4-piperidyl}-2-(3-15 pyridyl) benzenesulphonamide and its fumarate 20.3 ml of a 2M sodium carbonate solution are added at room temperature over the course of 2 hours to a solution of 3 g of the product obtained in Step A and 280 mg of tetrakis-(triphenylphosphine)palladium in 50 ml of toluene, and then, under argon, 1.3 g of diethylboran-3-ylpyridine in 25 ml of ethanol are added thereto. The reaction mixture is 20 then refluxed for 2 days, and subsequently diluted with water, extracted with ethyl acetate, dried over MgSC>4 and concentrated under reduced pressure. Chromatography of the residue over silica gel enables the expected product to be isolated. Meltins point (M.K.) : 94-103°C Elemental microanalysis: 25 C H N S % found 61.27 5.58 6.79 5.06 % calculated 61.27 5.47 6.91 5.28 -51 - EXAMPLE 50 ; A-{l-[3-(Benzofuran-3-yl)-2-hydroxypropyl]-4-piperidyl}-2-[3-aminophenyl]-benzenesulphonamide The product is obtained according to the process of Example 49 using 3-aminophenylboronic acid as reagent in Step B. Meltine point (M.K.) : 68-70°C Elemental microanalysis : C H N S % found 66.39 6.31 8.07 5.99 % calculated 66.51 6.18 8.11 6.34 EXAMPLE 51 : N-{1- [3-(Benzofuran-3-y l)-2-hy droxy propyl] -4-piperidy I}-3- [3-aminopheny I] -benzenesulphonamide The product is obtained according to the process of Example 49 using 3- bromobenzenesulphonic acid as reagent in Step A and using 3-aminophenylboronic acid as reagent in Step B. Meltine point (M.K.) : 68-78°C Elemental microanalysis: C H N S % found 66.27 6.43 7.98 6.38 % calculated 66.51 6.18 8.31 6.34 EXAMPLE 52 : JV-{l-[3-(Benzofuran-3-yl)-2-hydroxypropyl]-4-piperidyl}-3-(3-pyridyl)-benzenesulphonamide The product is obtained according to the process of Example 49, Steps A to B, using 3-bromobenzenesulphonic acid as reagent in Step A. Meltine point (M.K.) : 55-63°C -52- Elemental microanalysis: C H N S % found 66.02 6.03 8.41 6.19 % calculated 65.97 5.95 8.55 6.52 EXAMPLE 53 : N-{1- [3-(Benzofuran-3-y l)-2-fluoropropyl] -4-piperidyl}-5-isoquinolinesuIph onamide and its difumarate The product is obtained according to the process of Example 1 using the product of Preparation 30 as substrate instead of the product of Preparation 1. Meltine point (M.K.) : 197-204°C Elemental microanalysis: C H N S % found 56.76 4.86 6.00 4.50 % calculated 56.15 4.86 5.81 4.43 EXAMPLE 54 : 7V-{l-[2-(Benzofuran-3-vl)-l-(fluoromethyl)ethyl]-4-piperidyl}-5-isoquinoline-sulphonamide and its fumarate The product is obtained according to the process of Example 1 using the product of Preparation 31 as substrate instead of the product of Preparation 1. Meltine point (M.K.) : 143-153°C Elemental microanalysis: C H N S % found 59.72 5.48 6.82 5.00 % calculated 59.68 5.18 7.20 5.49 EXAMPLE 55 : 7V-{l-[2-(Benzofuran-3-yl)-ethyl]-4-piperidyl}-2-(3-pyridyl)benzenesulphonamide and its fumarate -53- Step A: N-{l-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-2-bromobenzene-sulphonamide The product is obtained according to the process of Step A of Example 49 using the product of Preparation 7 as substrate. 5 Meltins point (K) : 105-108°C Step B: N-{l-[2-(Benzofuran-3-yl)ethylJ-4-piperidyl}-2-bromo-N-[(2-methoxyethoxy)methyl]benzenesulphonamide 1.9 g of 60% sodium hydride in oil are added, at room temperature and under argon, to a solution of 15.8 g of the product obtained in Step A in 180 ml of tetrahydrofiiran. After 10 30 minutes' stirring, 5 ml of 2-methoxyethoxymethane chloride are added. After 5 hours at room temperature, the reaction mixture is concentrated under reduced pressure, taken up in dichloromethane, washed with water, dried and concentrated under reduced pressure to enable the expected product to be obtained. Step C: N-{1 -[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-N-[(2-methoxyethoxy)-15 methylJ-2-(3-pyridyl)benzenesulphonamide The product is obtained according to the process of Step B of Example 49 using the product obtained in the preceding Step B as substrate. Step D : N-{J-[2-(Benzofuran-3-yl)-ethyl]-4-piperidyl}-2-(3-pyridyl)benzene-sulphonamide and its fumarate 20 A solution of 1.7 g of the product obtained in Step C in 50 ml of ethanol and 50 ml of 6N hydrochloric acid is refluxed for 2 hours and then left for 12 hours at room temperature. The reaction mixture is then evaporated, diluted with water, adjusted to pH = 7 by the addition of an aqueous 10% sodium hydrogen carbonate solution, extracted with ethyl acetate, dried and evaporated to yield the expected product, which is converted to its 25 fumarate. Meltins point (M.K.) : 189-191°C -54- Elemental microanalysis: C H N S % found 62.34 5.52 7.26 5.46 % calculated 62.38 5.41 7.27 5.55 EXAMPLE 56 : TV- {1 - [2-(Benzofuran-3-y I)-ethyl] -4-piperidy 1} -2-[3-am inopheny 1] benzene-sulphonamide and its fumarate Step A: N-{l-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-N-[(2-methoxyethoxy)-methylJ-2-(3-aminophenyl)benzenesulphonamide The product is obtained according to the process of Example 50 using the product obtained in Step B of Example 55 as substrate. Step B: N-{l-(2-(Benzofuran-3-yl)-etkyl]-4-piperidyl}-2-[3-amino-phenyljbenzenesulphonamide and its fumarate The product is obtained according to the process of Step D of Example 55 using the product obtained in the preceding Step A as substrate. Meltins point (M.K.) : 97-102°C C H N S % found 62.71 5.89 6.71 5.02 % calculated 62.93 5.62 7.10 5.42 EXAMPLE 57: Ar-{l-[2-(Benzofuran-3-yl)-ethyl]-4-piperidyl}-3-(3-pyridyl)benzenesulphonamide and its fumarate The product is obtained according to, in succession, the process of Step A of Example 49 using the product of Preparation 7 as substrate and 3-bromobenzenesulphonyl chloride as -55- reagent, then according to the process of Step B of Example 55, then according to the process of Step B of Example 49 and finally according to the process of Step D of Example 55. Meltine point (M.K.) : 191-194°C Elemental microanalysis : C H N S % found 62.15 5.51 7.13 5.31 % calculated 62.38 5.41 7.27 5.55 EXAMPLE 58 : vV-{l-[2-(Benzofuran-3-yl)-ethyl]-4-piperidyl}-3-[3-aminophenyl]-benzene-sulphonamide and its dihydrochloride The product is obtained, in succession, according to the process of Example 50 using the product obtained in the second synthesis Step of Example 57 as substrate, and then according to the process of Step D of Example 55. The resulting product is converted into its dihydrochloride with a 2.5N solution of ethereal hydrogen chloride. Meltine point (M.K.) : 155-167°C Elemental microanalysis: C H N S CI % found 59.18 5.82 7.37 5.64 12.35 % calculated 59.12 5.70 7.66 5.85 12.93 EXAMPLE 59 : A^-({l-[2-(Benzofuran-3-yl)ethyI]-4-piperid\i}methyl)-A-methyl-l,23,4-tetrahydro-5-isoquinolinesulphonamide and its dihydrochloride 13.3 g of the product of Example 1 and 1.3 g of platinum oxide in 500 ml of acetic acid are hydrogenated under 5 bars at room temperature for 4 hours. The reaction mixture is then evaporated, taken up in water and ethyl acetate, rendered basic with IN sodium hydroxide solution, decanted, washed, dried and concentrated under reduced pressure. Chromatography over silica gel enables the expected product to be isolated. Meltine point (M.K.) : 162-174°C -56- Elemental microanalysis: C H N S CI % found 57.77 6.85 7.77 5.29 13.26 % calculated 57.77 6.53 7.77 5.93 13.12 5 EXAMPLE 60: 2-Acety l-JV-( {1 - [2-(benzofuran-3-y l)ethy 1] -4-piperidy 1} methyl)-A-methyl-l,2,3,4-tetrahydro-5-isoquinoIinesuIphonamide and its hydrochloride 2.2 g of the product obtained in Example 1 and 0.1 g of platinum oxide in 120 ml of acetic acid and 10 ml of acetic anhydride are hydrogenated under 5 bars, at room temperature, for • l0 12 hours. The expected product is isolated by chromatography over silica gel (CH2Cl2/Me0H/NH40H : 98/2/0.2). Meltine point (M.K.) : 108-110°C Elemental microanalysis: C H N S CI 15 % found 61.48 6.72 7.71 5.82 6.49 % calculated 61.58 6.64 7.69 5.87 6.49 EXAMPLE 61 : 5-{[({l-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-(methyl)amino]sulphonyl}-A-methyl-3,4-dihydro-2(i//)-isoquinoIinecarboxamide and its fumarate 20 2 g of the product of Example 59 in 4 ml of dichloromethane are added, at 10°C, to a solution of 0.25 g of methyl isocyanate in 1 ml of dichloromethane. After 45 minutes, the reaction mixture is washed, decanted, dried and evaporated. Chromatography over silica gel (dichloromethane/methanol: 95/5) enables the expected product to be isolated. Meltine point (M.K.) : 107-116°C 25 Elemental microanalysis : C H N S % found 59.82 6.40 8.57 4.95 % calculated 59.98 6.29 8.74 5.00 -57- FX AMPLE 62 : Ethyl 5-{[({l-[2-(benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-(methyl)amino]-sulphonyl}-3,4-dihydro-2(i//)-isoquinolinecarboxy!ate and its fumarate 0.41 ml of ethyl chloroformate is added to a solution, cooled to 0°C, of 2 g of the product 5 of Example 59 and 0.43 g of triethylamine in 7 ml of dichloromethane. After 2 hours at room temperature, the reaction mixture is diluted with water, decanted, dried and evaporated. Chromatography over silica gel (dichloromethane/methanol: 98/2) enables the expected product to be isolated. Meltine point (M.K.) : 109-113°C 10 Elemental microanalysis: C H N S % found 60.11 6.43 6.28 4.92 % calculated 60.44 6.30 6.41 4.89 15 EXAMPLE 63: 5-{[({l-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-(methyl)amino]sulphonyl}-3,4- dihydro-2(i//)-isoquinolinecarboxamide and its fumarate A solution of 1 g of the product of Example 59 in 10 ml of IN hydrochloric acid and 40 ml of water is adjusted to pH = 3 by the addition of 20% sodium hydroxide solution, and then 20 a solution of 0.187 g of potassium isocyanate in 0.5 ml of water is added at room temperature. After 20 minutes, the pH of the mixture has increased to pH = 6 and is returned to pH = 3 by the addition of IN hydrochloric acid. After 3 hours' reaction, the preceding operation is repeated. The reaction mixture is then heated for 3 hours at 50°C, and then 0.187 g of potassium isocyanate in 0.5 ml of water is added again, and the pH of 25 the mixture is maintained at pH = 3. After 2 hours, the reaction mixture is rendered basic with sodium hydroxide solution and extracted with dichloromethane. The expected product is isolated by customary treatment. Meltins point: 105-113°C -58- Elemental microanalysis: C H N S % found 59.41 6.11 8.94 5.12 % calculated 59.16 5.95 8.36 4.91 EXAMPLE 64: 5-{[({l-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-(methyl)amino]sulphonyI}-AyV-dimethyI-3,4-dihydro-2(i//)-isoquinolinecarboxamide and its fumarate 0.22 ml of N,N-diethylcarbamoyl chloride is added to a solution, cooled to 0°C, of 1 g of the product of Example 59, 0.24 g of triethylamine and 15 ml of dichloromethane. After 5 hours' reaction at room temperature, followed by 3 hours at reflux, 0.33 ml of triethylamine and 0.22 ml of N,N-diethylcarbamoyl chloride are added, and refluxing is maintained for 1 hour. After conventional treatment, the evaporation residue is chromato-graphed over silica gel (dichloromethane/methanol) enabling the expected product to be isolated. Meltine point (M.K.) : 115-120°C EXAMPLE 65 : Ar-({l-[2-(Benzofuran-3-vl)ethyl]-4-piperidyl}methyl)-i>V-methyl-2-(methylsulphonyl)- 1^3»4-tetrahydro-5-isoquinolinesulphonamide and its hydrochloride 0.27 ml of methanesulphonic acid chloride is added to a solution, cooled to 0°C, of 1.5 g of the product of Example 59 and 0.36 g of triethylamine in 15 ml of dichloromethane. After 10 minutes' reaction, the reaction mixture is treated in conventional manner, enabling the expected product to be obtained, which is converted to its hydrochloride with an ethereal hydrogen chloride solution. Meltine point (M.K.) : 223-233°C EXAMPLE 66 : iV-({l-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-7V-methyl-2-[(trifluoro-methyl)sulphonyl]-l,2,3>4-tetrahydro-5-isoquinolinesulphonamide and its fumarate -59- 0.36 ml of trifluoromethanesulphonic acid anhydride is added to a solution, cooled to -5°C, of 1 g of the product of Example 59 in 20 ml of dichloromethane, followed, after 1 hour, by 0.36 g of triethylamine and 0.36 ml of trifluoromethanesulphonic acid anhydride. After 12 hours' reaction at room temperature and customary treatment, chromatography over silica gel (dichloromethane/methanol: 98/2) enables the expected product to be isolated. Meltins point (M.K.) : 198-200°C Elemental microanalysis : C H N S % found 52.77 5.16 5.82 8.99 % calculated 52.02 5.07 5.87 8.96 EXAMPLE 67: Methyl 5- {[({1 - [2-(benzofuran-3-y l)ethy 1] -4-piperidy 1} methy l)-(methy l)am ino] -sulphonyl}-3,4-dihydro-2(i//)-isoquinoIinecarboxylate and its fumarate The product is obtained according to the process of Example 62 using methyl chloroformate as reagent. Meltins point (M.K.) : 110-115°C Elemental microanalysis: C H N S % found 59.39 5.96 6.46 4.73 % calculated 59.89 6.13 6.55 5.00 EXAMPLE 68 : Isopropyl 5-{[({l-[2-(benzofuran-3-yl)ethyl]-4-piperidyl}methyI)-(methyl)amino]-sulphonyl}-3,4-dihydro-2(7//)-isoquinolinecarboxylate and its fumarate The product is obtained according to the process of Example 62 using isopropyl chloroformate as reagent. Meltins point (M.K.) : 175-180°C -60- Elemenial microanalysis: C H N S % found 61.17 6.51 6.36 4.49 % calculated 60.97 6.47 6.27 4.79 EXAMPLE 69 : Tert-butyl 5- {[({1 -[2-(benzofuran-3-y l)ethyl]-4-piperidy 1} methy l)-(methy l)amino] -sulphonyl}-3,4-dihydro-2(J//)-isoquinoIinecarboxylate and its fumarate The product is obtained according to the process of Example 62 using tert-butyl chloroformate as reagent. Meltins point (M.K.) : 171-175°C Elemental microanalysis: C H N S % found 61.40 6.75 6.10 4.54 % calculated 61.48 6.63 6.14 4.69 EXAMPLE 70 : iV-({l-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-l,2,3,4-tetrahydro-5-isoquinolinesulphonamide and its dihydrochloride A solution of 6.6 g of the compound of Example 4, 150 ml of methanol, 3 ml of concentrated hydrochloric acid and 0.7 g of PtC>2 is hydrogenated under 5 bars for 5 hours. After conventional treatment, the resulting residue is taken up in methanol and the dihydrochloride is precipitated from a solution of methanolic hydrogen chloride. Meltins point (M.K.) : 125-135°C Elemental microanalysis: C H N S CI % found 57.01 6.39 7.78 5.78 13.39 % calculated 57.03 6.32 7.98 6.09 13.47 EXAMPLE 71 : 2-Acetyl-/V-({l-[2-(benzofuran-3-yl)ethyI]-4-piperidyl}methyl)-l,23,4-tetrahydro-5-isoquinolinesulphonamide and its fumarate -61 - 0.32 ml of acetic acid chloride is added to a solution, cooled to 0°C, of 2 g of the product of Example 70 and 2.8 ml of diisopropylethylamine. After 10 minutes' stirring at room temperature, the reaction mixture is treated in conventional manner. Chromatography over silica gel (dichloromethane/methanol : 95/5) enables the expected product to be isolated. Meltine point (M.K.) : 136-140°C Elemental microanalysis : C H N S % found 60.96 6.15 6.86 5.02 % calculated 60.87 6.10 6.87 5.24 EXAMPLE 72 : Ar-{l-[2-(Benzofuran-3-yl)ethyI]-4-piperidyI}-Ar-methyl-l,23^4-tetrahydro-5-isoquinolinesulphonamide The product is obtained according to the process of Example 70 using the product of Example 7 as substrate. Meltine point (M.K.) : 134-136°C Elemental microanalysis: C H N S % found 66.16 6.84 9.31 6.83 % calculated 66.20 6.89 9.26 7.07 EXAMPLE 73 : 2-Acetyl-A-{l-[2-(benzofuran-3-yl)ethylj-4-piperidyl}-7V-methyl-l,2,3,4-tetrahydro- 5-isoquinolinesulphonamide The product is obtained according to the process of Example 71 using the product of Example 72 as substrate. Meltine point (M.K.) : 118-120°C -62- Eiemental microanalysis : % found % calculated C H 65.31 6.70 65.43 6.71 N S 8.31 6.14 8.48 6.47 EXAMPLE 74 : 2-Trifluoroacetyl-Ar-({l-[2-(benzofuran-3-yI)ethyI]-4-piperidyl}methyI)-7V-methyl-l,2,3>4-tetrahydro-5-isoquinolinesulphonamide and its fumarate The product is obtained according to the process of Example 66 using the product of Example 72 as substrate, and using trifluoromethylacetic acid anhydride as reagent. Meltine point (M.K.) : 102-106°C Elemental microanalysis : C H N S % found 56.71 5.32 6.27 4.59 % calculated 56.55 5.34 6.18 4.72 EXAMPLE 75 : Ar-{l-[2-(Benzofuran-3-yl)ethvl]-4-piperidyl}-l,23,4-tetrahydro-5-isoquinoline-sulphonamide and its hemifumarate The product is obtained according to the process of Example 70 using the product of Example 8 as substrate. Meltins point (M.K.) : 286-288°C Elemental microanalysis: C H N S % found 62.73 6.36 8.28 6.33 % calculated 62.76 6.28 8.44 6.44 EXAMPLE 76 : 2-Acetyl-Ar-{l-[2-(benzofuran-3-yl)ethyl]-4-piperidyl}-l,23>4-tetrahydro-5-isoquinolinesulphonamide -63- The product is obtained according to the process of Example 71 using the product of Example 75 as substrate. Meltine point (M.K.) : 70-80°C Elemental microanalysis : C H N S % found 64.87 6.20 8.65 6.40 % calculated 64.84 6.49 8.72 6.66 EXAMPLE 77: 2-Ethyl-Ar-({l-[2-(benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-A-methyM,2,3,4-tetrahydro-5-isoquinoIinesulphonamide and its camphosulphonate A solution of 1 g of the product of Example 60 in 60 ml of tetrahydrofiiran is added to a suspension of 0.15 g of lithium aluminium hydride in 25 ml of tetrahydrofiiran at reflux. After 1 hour at reflux followed by cooling, the reaction mixture is hydrolysed with 0.1 ml of water, 0.08 ml of 20% sodium hydroxide solution and 0.37 ml of water. After conventional treatment, chromatography over silica gel (dichloromethane/methanol : 90/10) enables the expected product to be isolated. Meltine point (M.K.) : 70-80°C EXAMPLE 78 : Methyl 5-{[({l-[2-(5-fluoro-benzofuran-3-yl)ethyI]-4-piperidyI}methyl)-(methyl)amino]sulphonyl}-3,4-dihydro-2(///)-isoquinolinecarboxylate and its fumarate Step A : N-[(l-Benzyl-4-piperidyl)methyl]-N-methyl-5-isoquinolinesulphonamide The product is obtained according to the process of Example 1 using 7V-[(l-benzyl-4-piperidyl)methyl]-iV-methylamine instead of the product of Preparation 1. Step B: N-f (1 -Benzyl-4-piperidyl) methylf-N-methy 1-1,2,3,4-tetrahydro-5-isoquinolinesulphonamide -64- The product is obtained according to the process of Example 70 using the product obtained in the preceding Step A. Step C: Methyl 5-{[[(l-benzyl-4-piperidyl)methyl](methyl)amino]sulphonyl}-3,4-dihydro-2(lH)-isoquinolinecarboxylate The product is obtained according to the process of Example 60 using the product obtained in the preceding Step B, and using methyl chloroformate as reagent. Step D: Methyl 5-{[[(4-piperidyl)methyl](methyl)amino]sulphonyl}-3,4-dihydro-2(lH)-isoquinolinecarboxylate A mixture of 5.6 g of the product obtained in Step C, 3.7 g of ammonium formate and 0.56 g of 10% Pd/C in 120 ml of methanol is refluxed for 3 hours, then filtered over Celite and evaporated to dryness, enabling the expected product to be isolated. Step E: Methyl 5-{[({l-[2-(5-fluoro-benzofuran-3-yl)ethyl]-4-piperidyl}-methyl)-(methyl)aminoJsulphonyl}-3,4-dihydro-2(lH)-isoquinolinecarboxylate and its fumarate A mixture of 2 g of the product obtained in Step D, 1.26 g of 2-(5-fluorobenzofuran-3-yl)-1-bromoethane, 1.4 g of potassium carbonate and 30 ml of acetonitrile is heated at 50°C for 2 hours. After evaporation to dryness, the residue is taken up in water and ethyl acetate and subjected to customary treatment. Chromatography over silica gel (ethyl acetate) enables the expected product to be isolated, which is converted into its fumarate. Meltins point (M.K.) : 110-115°C Elemental microanalysis: C H N S % found 58.31 5.65 6.35 4.58 % calculated 58.26 5.81 6.37 4.86 -65- EXAMPLE 79: Ethyl 5- {[({1 - [2-(5-fluoro-benzofuran-3-y I)ethy 1] -4-piperidy 1} methyl)-(methy 1)-amino]sulphonyl}-3,4-dihydro-2(i//)-isoquinolinecarboxylate and its fumarate The product is obtained according to the process of Example 78 in Steps A to E, using ethyl chloroformate as reagent in Step C. Meltine point (M.K.) : U5-120°C Elemental microanalysis: C H N S % found 58.79 6.13 6.12 4.51 % calculated 58.82 6.00 6.24 4.76 EXAMPLE 80 : Isopropyl 5- {[({1 - [2-(5-fluoro-benzofuran-3-y l)ethy 1] -4-piperidy 1} m ethy 1)-(methyl)amino]sulphonyl}-3,4-dihydro-2-(//)-isoquinolinecarboxylate and its fumarate The product is obtained according to the process of Example 78, Steps A to E, using isopropyl chloroformate as reagent in Step C. Meltine point (M.K.) : 135-145°C Elemental microanalysis: C H N S % found 59.30 6.06 6.14 4.47 % calculated 59.38 6.15 6.11 4.66 EXAMPLE 81 : Ethyl 5-{[({l-[2-(benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl}ethyl)amino]-sulphonyl}-3,4-dihydro-2(l//)-isoquinolinecarboxylate and its fumarate The product is obtained according to the process of Example 78, Steps A to E, using 4-aminomethyl-l-benzylpiperidin-4-ol as substrate in Step A, ethyl chloroformate in Step C, and 2-(benzofuran-3-yl)ethanol mesylate in Step E. Meltine point (M.K.) : 180-185°C -66- Elemental microanalysis: % found % calculated C H 58.17 5.99 58.44 5.98 N S 6.30 4.56 6.39 4.87 EXAMPLE 82 : Ethyl 5- {[({1 - [2-(5-fluoro-benzofuran-3-y l)ethy I] -4-hydroxy-4-piperidy 1}-methyl)amino]sulphonyl}-3,4-dihydro-2(l//)-isoquinolinecarboxylate and its fumarate The product is obtained according to the process of Example 81, using 2-(5-fluoro-benzofuran-3-yl)ethanol mesylate as reagent in Step E. Meltins point (M.K.) : 165-175°C Elemental microanalysis: C H N S % found 56.82 5.69 6.13 4.40 % calculated 56.88 5.67 6.22 4.75 EXAMPLE 83 : 2-Acetyl-N-{(l-[2-(benzofuran-3-yl)eth\i]-4-piperid\i-4-hydroxy)methyl}-l,23,4-tetrahydro-5-isoquinolinesulphonamide and its mesylate The product is obtained according to the process of Example 81, using acetyl chloride instead of ethyl chloroformate as reagent in Step C. Meltins point (M.K.) : 201-206°C Elemental microanalysis: C H N S % found 55.20 6.17 6.73 10.91 % calculated 55.34 6.14 6.91 10.55 EXAMPLE 84 : Ethyl 5- {[({1 - [2-(benzofuran-3-yl)ethy 1] -4-hydroxy-4-piperidy 1} methy 1)-(methyl)amino]sulphonyl}-3,4-dihydro-2-(l//)-isoquinolinecarboxylate -67- The product is obtained according to the process of Example 83, using l-benzyl-4-(methylamino)methyl-piperidin-4-ol as substrate in Step A. Meltins point (M.K.) : 125-130°C Elemental microanalysis: C H N S % found 62.76 6.76 7.56 5.90 % calculated 62.68 6.71 8.56 5.77 EXAMPLE 85 : 5-{[{l-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}amino]sulphonyl}-3,4-dihydro-2(l/f)-isoquinolinecarboxamide The product is obtained according to the process of Example 63 using the compound of Example 75 as substrate. Meltins point (M.K.) : 198-201°C EXAMPLE 86 : 7V-{l-|2-(l//-Inden-3-yl)ethyl]-4-piperidvl}-A-methyl-l,2,3>4-tetrahydro-5-isoquinolinesulphonamide The product is obtained according to the process of Example 59 using the compound of Example 5 as substrate. Meltins point (M.K.) : 210-214°C EXAMPLE 87 : N-{l-[3-(Benzofuran-3-yl)-2-hydroxypropyl]-4-piperidyl}-3-[2-aminophenyl]-benzenesulphonamide and its dihydrochloride The product is obtained according to the process of Example 49 using 3-bromobenzenesulphonic acid in Step A and using 2-aminophenylboronic acid in Step B. The dihydrochloride is obtained by the action of a solution of ethereal hydrogen chloride. -68- MeMns point (M.K.): 145-148°C EXAMPLE 88: N-{l-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-4-bromo-5-isoquinolinesulphonamide and its fumarate 5 The product is obtained according to the process of Example 1 using the compound of Preparation 7 as substrate instead of the compound of Preparation 1, and using the compound of Preparation 33 instead of 5-isoquinolinesulphonyl chloride hydrochloride. The resulting product is converted to its fumarate. Meltins point (M.K.) : 234-236°C 10 EXAMPLE 89 : N-{l-[2-(Benzofuran-3-yl)ethyI]-4-piperidyl}-4-fluoro-5-isoquinolinesulphonamide and its fumarate The product is obtained according to the process of Example 1 using the compound of 15 Preparation 7 as substrate instead of the compound of Preparation 1, and using the compound of Preparation 34 instead of 5-isoquinolinesulphonyl chloride hydrochloride. The resulting product is converted to its fumarate. Meltins point (M.K.) : 219-221°C PHARMACOLOGICAL STUDIES OF THE COMPOUNDS OF THE INVENTION 20 Under standard in vitro conditions, relaxation of aortic rings caused by acetylcholine (ACh), which relaxation is totally dependent upon the presence of endothelium, reflects the production of NO (stimulated by ACh), which by diffusing to smooth muscle cells brings about arterial relaxation (.Nature, 1980, 288, 373). The compounds of the invention were tested in respect of two models involving two 25 different mechanisms implicated in the endothelial dysfunction observed in pathology : - the first model consists of inducing inhibition of the relaxation due to ACh by blocking the enzymatic activity (endothelial NOS) responsible for the production of NO. -69- - the second model consists of inducing oxidative stress in vitro using an enzymatic system that generates O2" (xanthine oxidase -XO and hypoxanthine - Hypo). Vascular protective effects with respect to endothelial dysfunction induced by an inhibitor of NOS The thoracic aorta of a Wistar rat (325-375 g), anaesthetised by the intraperitoneal route using sodium pentobarbital (30 mg/kg), is removed and dissected into rings of 3mm in length. Each ring is suspended from an isometric tension sensor connected to a recording system and the initial tension applied is 2.5 g. The physiological solution used, which is thermostatically maintained at 37°C, and oxygenated (95% O2 + 5% CO2), comprises (in mM) : NaCl 112.0, KC1 5.0, CaCl2 2.5, KH2PO4 1.0, MgS04 1.2, NaHC03 25.0, glucose 11.5, Ca-EDTA 0.016. After a 90-minute stabilisation period, the preparations are contracted using phenylephrine (PHE 10"^ M) and relaxed by adding 10"^ M of acetylcholine in order to verify the integrity of the endothelial layer. If that is confirmed, the preparations are rinsed and a concentration of the test product (or its solvent) is added to the medium, followed by 3.10"7 M of NG-nitro-L-arginine (LNA). The preparations are again contracted using phenylephrine and, after 30 minutes, the relaxations due to acetylcholine (ACh - 10"^M to 10*5 M) are assessed in the presence of indomethacin (10"^M). The relaxation values are expressed as a percentage relative to the maximum contraction caused by PHE. The protective effects of the compounds with respect to the endothelial dysfunction correspond to the difference between the percentages of maximum relaxation observed in the presence or absence of product. By way of example, the compound of Example 8 at 3x10"^ M inhibits the endothelial dysfunction induced by LNA by 23 %. EXAMPLE 91 : Vascular protective effects with respect to endothelial dysfunction induced by a system generating O2" -70- This protocol, carried out on aortic rings of New Zealand rabbits (2.5-3 kg) is comparable to the previous protocol except for the following points : the initial tension applied is 5 g and the combination XO (3 mU/ml) - Hypo (10*4 M) is used instead of the LNA. By way of example, the compound of Example 8 at 3x10*9 M inhibits the endothelial dysfunction induced by the XO-Hypo combination by 28.3 %. EXAMPLE 92 : Involvement of the NO route in the vascular protective effects detected : assessment of aortic production of cGMP. By diffusing to the smooth muscle cells, the NO produced by the endothelial cells activates soluble guanylate cyclase, which brings about an increase in cyclic GMP which is responsible for relaxation. The level of that mediator in rat aortic rings was therefore determined in order to demonstrate that the protective effects of the compounds with respect to endothelial dysfunction are mediated by an increase in the availability of NO. The rat aortic rings are prepared as previously. Assessment is made of the effects of a 30-minute incubation of the compounds of the invention at different concentrations on the production of cGMP stimulated by ACh (10*5 m - 1 minute) in the presence of LNA (3x10*6 M). The experiments are carried out in the presence of isobutylmethylxanthine (10*5 M) in order to avoid degradation of the cGMP by phosphodiesterases. The rings are frozen in liquid nitrogen and maintained at -80°C until the assay is carried out. The cGMP content is assessed by radioimmunoassay and expressed in relation to the amount of protein contained in the tissue (assay by the Bradford method). By way of example, the compound of Example 8 at 3x10*9 m increases the production of cGMP stimulated by ACh in the presence of LNA by 142.7 % EXAMPLE 93 : Pharmaceutical composition - tablet -71 - Formulation for the preparation of 1000 tablets containing a dose of 10 mg Compound of Example 8 10 g Hydroxypropylcellulose 2 g Polyvinylpyrrolidone 2 g Wheat starch 10 g Lactose 100 g Magnesium stearate 3 g </div>

Claims

<div class="application article clearfix printTableText" id="claims"> -72- WHAT WE CLAIM IS: 1! Compounds of formula (I): W-SO—NR—U / \ N-V- wherein: Ri represents a hydrogen atom or a linear or branched (Ci-C6)alkyl group, R2a and R21,, which may be identical or different, each independently of the other represents a group selected from a hydrogen atom, a halogen atom, a linear or branched (Ci-C6)alkyl group, a hydroxy group, a linear or branched (Ci-C6)alkoxy group, a linear or branched (Ci-C6)trihaloalkyl group, a cyano group, a nitro group, an amino group, a linear or branched (Ci-C6)alkylamino group, and a di-(Ci-C6)alkyl-amino group in which each alkyl moiety is linear or branched, R3 represents a hydrogen atom or a hydroxy group, X represents an oxygen atom or a methylene group, V represents a linear or branched (Ci-C6)alkylene chain optionally containing one or more unsaturations and being optionally substituted by one or more identical or different groups selected from halogen atoms, hydroxy groups and linear or branched (Ci-Cg)alkoxy groups, U represents a bond or a linear or branched (Ci-C6)alkylene chain, W represents a group selected from aryl and heteroaryl, each of those groups being optionally substituted by one or more identical or different groups selected from halogen atoms, linear or branched (Ci-C6)alkyl groups, hydroxy groups, linear or branched (Ci-C6)alkoxy groups, linear or branched (Ci-C6)trihaloalkyl groups, oxo groups, cyano groups, nitro groups, amino groups, linear or branched (Ci-Cg)-alkylamino groups, di-(Ci-C6)alkylamino groups in which each alkyl moiety is linear or branched, pyridyl groups, linear or branched (Ci-C6)alkylcarbonyl groups, aminocarbonyl groups (the amino moiety being optionally substituted by one or two identical or different linear or branched (Ci-C6)alkyl groups), linear or branched -73- (Ci-C6)alkoxycarbonyl groups, linear or branched (Ci-C6)trihaloalkylcarbonyl groups, linear or branched (Ci-C6)alkylsulphonyl groups, and linear or branched (Ci-Ce)-trihaloalkylsulphonyl groups, their isomers, their hydrates, their solvates and addition salts thereof with a 5 pharmaceutically acceptable acid or base, it being understood that: - "aryl group" is understood to mean a group selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl and indenyl, - "heteroaryl group" is understood to mean a monocyclic aromatic or bicyclic system 10 having from 5 to 12 ring members and containing from 1 to 3 identical or different hetero atoms selected from oxygen, nitrogen and sulphur, and in the case of a bicyclic system one of the rings has an aromatic character, it being possible for the other ring to be aromatic or partially hydrogenated. 21 Compounds of formula (I) according to claim 1, characterised in that X represents an 15 oxygen atom, their isomers, their hydrates, their solvates and addition salts thereof with a pharmaceutically acceptable acid. 31 Compounds of formula (I) according to claim 1, characterised in that Ri represents a hydrogen atom or a methyl group, their isomers, their hydrates, their solvates and addition salts thereof with a pharmaceutically acceptable acid. 20 41 Compounds of formula (I) according to any one of claims 1 to 3, characterised in that they represent compounds of formula (i/A) : W-SO—NH—U \ N—V- j (I/A) wherein W, U, V, R2a and R2b are as defined for formula (I), their isomers, their hydrates, their solvates and addition salts thereof with a pharmaceutically acceptable acid. 5/ Compounds of formula (I) according to claim 1, characterised in that W represents an isoquinolin-5-yl group, their isomers, their hydrates, their solvates and addition salts thereof with a pharmaceutically acceptable acid. 61 Compounds of formula (I) according to claim 1, characterised in that W represents a l,2,3,4-tetrahydro-isoquinolin-5-yl group optionally substituted in the 2-position by a group of formula -C(0)-A wherein A represents a group selected from linear or branched (Ci-C6)alkyl, amino (itself optionally substituted by one or two identical or different linear or branched (Ci-C6)alkyl groups), linear or branched (Ci-C6)alkoxy, trifluoromethyl, linear or branched (Ci-C6)alkylsulphonyl, and trifluoromethylsulphonyl, their isomers, their hydrates, their solvates and addition salts thereof with a pharmaceutically acceptable acid. 7/ Compounds of formula (I) according to claim 4, characterised in that they represent compounds of formula (I/A) as defined hereinbefore wherein U, V, R2a and R2b are as defined for formula (I) and W represents an isoquinolin-5-yl group, their isomers, their hydrates, their solvates and addition salts thereof with a pharmaceutically acceptable acid. 8/ Compounds of formula (I) according to claim 4, characterised in that they represent compounds of formula (I/A) as defined hereinbefore wherein U, V, R2a and R2b are as defined for formula (I) and W represents a l,2,3,4-tetrahydroisoquinolin-5-yl group optionally substituted in the 2-position by a group of formula -C(0)A wherein A is as defined hereinbefore, their isomers, their hydrates, their solvates and addition salts thereof with a pharmaceutically acceptable acid. 9/ Compounds of formula (I) according to claim 1 which are : - jV-{l-[2-(benzofuran-3-yl)ethyl]-4-piperidyl}-(isoquinolin-5-yl)sulphonamide, - ethyl 5-{[({(l-[2-(benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-(methyl)amino]-sulphonyl} -3,4-dihydro-2( 1 //)-isoquinolinecarboxylate, - jV-({2-[2-benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl}ethyl)-5-isoquinoline-sulphonamide, - N-( {1 - [2-(benzofuran-3 -yl)ethyl] -4-hydroxy-4-piperidyl} methyl)-vV-methyl-2,1,3- -75- benzoxadiazole-4-sulphonamide, and - isopropyl 5-{[({ l-[2-(benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-(methyl)amino]-sulphonyl} -3,4-dihydro-2( 1 //)-isoquinolinecarboxylate. 101 Process for the preparation of compounds of formula (I) according to claim 1, characterised in that there is used as starting material a compound of formula (II) : *2. ^ n (II) R, ■j*Y +v, o 10 wherein X, R2a and R2b are as defined for formula (I), V i represents a bond or a linear or branched (Ci-Cs)alkylene chain optionally containing one or more unsaturations, R5 represents a hydrogen atom, a chlorine atom, a hydroxy group or a linear or branched (Ci-C6)alkoxy group, which compounds of formula (II) are reacted : 15 20 4 either with a compound of formula (III/A): "OC to yield compounds of formula (IV): -o \ N. / (III/A) "iPl Raa (IV) 0 " ^ wherein R2a, R2b, X and V1 are as defined hereinbefore, the ketal function of which compounds of formula (IV) is deprotected in accordance with conventional techniques of organic synthesis, and which are then reacted under conditions of reductive amination with a compound of formula (V) : R'i - NH2 (V) wherein R'i represents a linear or branched (Ci-C6)alkyl group, to yield compounds of formula (VI/A) : -76 R'—NH O " Rab wherein R'i, R2a, R2b, X and Vi are as defined hereinbefore, (VI/A) 4 or with a compound of formula (III/B): NHBoc (III/B) wherein Boc represents a terf-butoxycarbonyl group, to yield compounds of formula (VII) : BocHN (VII) 0 wherein Boc, R2a, R2t» X and Vi are as defined hereinbefore, the terminal amine function of which compounds of formula (VII) is deprotected to yield compounds of 10 formula (VI/B): Aa (VI/B) o H2N~A /S^VHFT O wherein R2a, R2b, Vj and X are as defined hereinbefore, 15 the totality of the compounds of formulae (VI/A) and (VI/B) constituting the compounds of formula (VI) : ,— /Vr R. - NH \ /NVVrt" I —7 i (VI) 0 " Rab wherein Ri is as defined for formula (I) and R2a, R2b, X and Vi are as defined hereinbefore, which compounds of formula (VI) are treated with one of the reducing agents currently used in organic synthesis to reduce amide functions, to yield compounds of formula (VIII): -77- R.-NH (VIII) wherein Ri, Vi, X, R2a and R2b are as defined hereinbefore, which compounds of formula (VIII) are treated with a compound of formula (IX) : W - S02C1 (IX) wherein W is as defined for formula (I), to yield compounds of formula (I/a), a particular case of the compounds of formula (I): W-SO—N \ N Vr ' V 1 (I/a) wherein W, Ri, Vi, X, R2aand R2b are as defined hereinbefore, 4 or with a compound of formula (III/C): 10 15 ho2c-u \ J nh (III/C) wherein Ui represents a bond or a linear or branched (Ci-Cs)alkylene chain, to yield compounds of formula (X): ho2c-u, (X) 0 "" Rab wherein Ui, V], X, R2a and R2b are as defined hereinbefore, which compounds of formula (X) are treated with ammonium hydroxide or with a compound of formula (V) as defined hereinbefore in the presence of a coupling agent, such as dicyclo-hexylcarbodiimide, carbonyldiimidazole or 1,1,1,3,3,3-hexamethyldisylazane, to yield compounds of formula (XI): ,R* n ^ ,UT rj - nh Y o Y ' (XI) o Rab 10 -78- wherein Rj is as defined for formula (I), and Ui, Vi, X, R2a and R2b are as defined hereinbefore, which compounds of formula (XI) are reduced in accordance with conventional conditions of organic synthesis, to yield compounds of formula (XII) : , w* vVr r-nh-u2 V J (XII) wherein U2 represents a linear or branched (Ci-C6)alkylene chain, and Ri, Vj, X, R2a and R2b are as defined hereinbefore, which compounds of formula (XII) are reacted with a compound of formula (IX), as described hereinbefore, to yield compounds of formula (I/b), a particular case of the compounds of formula (I): f1 w—SO—N—u2 N"^V: J hT^I X^< R23 (i/b) *2b wherein W, Ri, U2, Vi, X, R2a and R2b are as defined hereinbefore, 4 or the terminal carbonyl group of which compounds of formula (II), which group is substituted by a group R'5 having the meanings of R5 as defined hereinbefore with the 15 exception of the meaning "chorine atom", is reduced,-the resulting hydroxy group of which is then replaced by a halogen atom, such as CI, Br or I, using customary techniques of organic chemistry, to yield compounds of formula (II/B) : R, R. 4-V - Hal (II/B) 2b x wherein X and V are as defined for formula (I) and Hal represents a halogen atom, 20 which compound of formula (II/B) is added to a compound of formula (III/D): ,OH *Ta (III/D) U2 - NH - C02Et wherein U2 is as defined hereinbefore, 79- to yield compounds of formula (XIII): Et02C - NH - U2 HO \ / \ X ■Raa (XIII) wherein U2, V, X, R2a and R2b are as defined hereinbefore, which compounds of formula (XIII) are treated with a reducing agent or with a strong alkaline base, to yield compounds of formula (XIV) : ,*2a (XIV) Ria - NH - u2 HO \ / ^ X wherein Ria represents a hydrogen atom or a methyl group, and U2, V, X, R2a and R2b are as defined hereinbefore, which compounds of formula (XIV) are treated with a compound of formula (IX), to yield compounds of formula (I/c), a particular case of the compounds of formula (I): Ria Aa (I/C) W - S02 - N - u2 HO / N—V-j- R*. wherein W, Ria, U2, V, X, R2a and R2b are as defined hereinbefore, i or which compound of formula (II), in the particular case when R5 represents a hydrogen atom and Vi has the meaning V'i representing a linear or branched (Ci-C4)alkylene chain, is treated with trimethylsulphoxonium iodide in the presence of sodium hydride in dimethyl sulphoxide, to yield compounds of formula (II/C) : *2. *2, (II/C) wherein R2a, R2b, X and V'i are as defined hereinbefore, which compounds of formula (II/C) are reacted with any one of the compounds of formulae (III/A), (III/B) and (III/C), the resulting intermediates then being deprotected and functionalised in accordance with the respecti^ mithdds de^cribed^ereinbefore, to yield compounds of formula (XV) : R, -NH-U -I ^*—\ -^%2' X-y WHt- , OH X^^^ (XV) wherein Ri, U, X, R2a and R2b are as defined hereinbefore and V'i is as defined hereinbefore, 4 or which compound of formula (II), in the particular case when it represents a compound of formula (II/D): R* o R2, Br am X' wherein R2a, R2b and X are as defined for formula (I), is reacted with any one of the compounds of formulae (III/A), (III/B) and (III/C), the resulting intermediates then being deprotected and functionalised in accordance with the respective methods described hereinbefore, to yield compounds of formula (XVI): Rj -NH-U- "\ N / O —^ R*. (XVI) R* wherein Ri, U, X, R2a and R2b are as defined hereinbefore, which compounds of formula (XVI) are reduced in conventional manner to yield compounds of formula (XVII) : R, - NH - U- \ N / HO Raa (XVII) R2b wherein Rls U, X, R2a and R2b are as defined hereinbefore, the totality of the compounds of formulae (XV) and (XVII) constituting the compounds of INTELLECTUAL PROPERTY OFFICE OF N.Z. - 6 JUN 2001 RECEIVED -81 - formula (XVIII): 10 15 20 rj - nh - u (XVIII) wherein Ri, U, X, R2a and R2b are as defined hereinbefore, and V'ia represents a bond or a linear or branched (Ci-C4)alkylene chain, the hydroxy function of which compounds of formula (XVIII) is replaced, if desired, by a halogen atom, in accordance with conventional conditions of organic synthesis, to yield compounds of formula (XIX): R, -NH-U- \ N- y -V' la Hal ~iT* (XIX) wherein Hal represents a halogen atom, and Rj, I], V'Ia, X, R2a and R2b are as defined hereinbefore, the totality of the compounds of formulae (XVIII) and (XIX) being reacted with a compound of formula (IX), as described hereinbefore, to yield compounds of formula (I/d), a particular case of the compounds of formula (I): R, w-so2-n-u- N y V' la -XAW (i/d) *2b wherein W, Ri, U, X, R2a and R2b are as defined for formula (I), V'ia is as defined hereinbefore and R^ represents a hydroxy group or a halogen atom, which compounds of formula (I/d), in the particular case when R6 represents a hydroxy group, are subjected to the action of an alkylating agent in accordance with conventional conditions of organic chemistry, to yield compounds of formula (I/e), a particular case of the compounds of formula (I): 82- (I/e) wherein W, Rl5 U, V'ja, X, R2a and R2b are as defined hereinbefore and R7 represents a linear or branched (Ci-C6)alkyl group, which compounds of formulae (I/a) to (I/e) constitute the totality of the compounds of the invention, which are purified, if necessary, in accordance with conventional purification techniques, which may be separated, if desired, into their different isomers in accordance with a conventional separation technique, the substituents R2a and R2b of which and those of the group W being transformed in accordance with conventional methods of organic synthesis used in the field of aromatic chemistry, the W group of which, when it is a bicyclic system, is reduced, if desired, to yield bicyclic W groups, one of whose rings is partially hydrogenated and which may then be substituted in accordance with conventional conditions of organic chemistry, and which are converted, if desired, into their addition salts with a pharmaceutically acceptable acid or base, and which may be in the form of hydrates or solvates. Ill Pharmaceutical compositions comprising as active ingredient at least one compound of formula (I) according to any one of claims 1 to 9, alone or in combination with one or more inert non-toxic pharmaceutically acceptable excipients or carriers. 12/ Pharmaceutical compositions according to claim 11 comprising at least one active ingredient according to any one of claims 1 to 9, for use as a medicament for the treatment of diseases or pathological conditions in which an endothelial dysfunction is known. 13/ Pharmaceutical compositions according to claim 11 comprising at least one active ingredient according to any one of claims 1 to 9, for use as a medicament for preventing the development, extension and complications of atherosclerotic lesions, for preventing vascular complications after vascular bypass, vascular dilatation, vascular repermeabilisation and heart transplantation, or for treating myocardial or peripheral ischaemia, cardiac insufficiency and pulmonary arterial hypertension. . . ^ ,0 3 * 3 Jf Ao((2_ gT intell^c 11 'a' 0-3'—'jy j th© Qutnortssd agents c m ^ A J PARK </div>